Publications by authors named "Patricia Jennings"

135 Publications

Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly.

Neuron 2021 01 20;109(2):241-256.e9. Epub 2020 Nov 20.

Division of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds LS9 7TF, UK.

Autosomal-recessive cerebellar hypoplasia and ataxia constitute a group of heterogeneous brain disorders caused by disruption of several fundamental cellular processes. Here, we identified 10 families showing a neurodegenerative condition involving pontocerebellar hypoplasia with microcephaly (PCHM). Patients harbored biallelic mutations in genes encoding the spliceosome components Peptidyl-Prolyl Isomerase Like-1 (PPIL1) or Pre-RNA Processing-17 (PRP17). Mouse knockouts of either gene were lethal in early embryogenesis, whereas PPIL1 patient mutation knockin mice showed neuron-specific apoptosis. Loss of either protein affected splicing integrity, predominantly affecting short and high GC-content introns and genes involved in brain disorders. PPIL1 and PRP17 form an active isomerase-substrate interaction, but we found that isomerase activity is not critical for function. Thus, we establish disrupted splicing integrity and "major spliceosome-opathies" as a new mechanism underlying PCHM and neurodegeneration and uncover a non-enzymatic function of a spliceosomal proline isomerase.
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http://dx.doi.org/10.1016/j.neuron.2020.10.035DOI Listing
January 2021

Latent Variable Interactions With Ordered-Categorical Indicators: Comparisons of Unconstrained Product Indicator and Latent Moderated Structural Equations Approaches.

Educ Psychol Meas 2020 Apr 24;80(2):262-292. Epub 2019 Jul 24.

Fordham University, Bronx, NY, USA.

Methods to handle ordered-categorical indicators in latent variable interactions have been developed, yet they have not been widely applied. This article compares the performance of two popular latent variable interaction modeling approaches in handling ordered-categorical indicators: unconstrained product indicator (UPI) and latent moderated structural equations (LMS). We conducted a simulation study across sample sizes, indicators' distributions and category conditions. We also studied four strategies to create sets of product indicators for UPI. Results supported using a parceling strategy to create product indicators in the UPI approach or using the LMS approach when the categorical indicators are symmetrically distributed. We applied these models to study the interaction effect between third- to fifth-grade students' social skills improvement and teacher-student closeness on their state English language arts test scores.
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http://dx.doi.org/10.1177/0013164419865017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047260PMC
April 2020

Unraveling Allostery in a Knotted Minimal Methyltransferase by NMR Spectroscopy.

J Mol Biol 2020 04 2;432(9):3018-3032. Epub 2020 Mar 2.

University of California, San Diego, 9500 Gilman Drive, Natural Science Building #3110, La Jolla, CA 92093, USA. Electronic address:

The methyltransferases that belong to the SpoU-TrmD family contain trefoil knots in their backbone fold. Recent structural dynamic and binding analyses of both free and bound homologs indicate that the knot within the polypeptide backbone plays a significant role in the biological activity of the molecule. The knot loops form the S-adenosyl-methionine (SAM)-binding pocket as well as participate in SAM binding and catalysis. Knots contain both at once a stable core as well as moving parts that modulate long-range motions. Here, we sought to understand allosteric effects modulated by the knotted topology. Uncovering the residues that contribute to these changes and the functional aspects of these protein motions are essential to understanding the interplay between the knot, activation of the methyltransferase, and the implications in RNA interactions. The question we sought to address is as follows: How does the knot, which constricts the backbone as well as forms the SAM-binding pocket with its three distinctive loops, affect the binding mechanism? Using a minimally tied trefoil protein as the framework for understanding the structure-function roles, we offer an unprecedented view of the conformational mechanics of the knot and its relationship to the activation of the ligand molecule. Focusing on the biophysical characterization of the knot region by NMR spectroscopy, we identify the SAM-binding region and observe changes in the dynamics of the loops that form the knot. Importantly, we also observe long-range allosteric changes in flanking helices consistent with winding/unwinding in helical propensity as the knot tightens to secure the SAM cofactor.
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http://dx.doi.org/10.1016/j.jmb.2020.02.029DOI Listing
April 2020

The Pierced Lasso Topology Leptin has a Bolt on Dynamic Domain Composed by the Disordered Loops I and III.

J Mol Biol 2020 04 17;432(9):3050-3063. Epub 2020 Feb 17.

The Department of Chemistry, University of Hawaii, Manoa, Honolulu, USA. Electronic address:

Leptin is an important signaling hormone, mostly known for its role in energy expenditure and satiety. Furthermore, leptin plays a major role in other proteinopathies, such as cancer, marked hyperphagia, impaired immune function, and inflammation. In spite of its biological relevance in human health, there are no NMR resonance assignments of the human protein available, obscuring high-resolution characterization of the soluble protein and/or its conformational dynamics, suggested as being important for receptor interaction and biological activity. Here, we report the nearly complete backbone resonance assignments of human leptin. Chemical shift-based secondary structure prediction confirms that in solution leptin forms a four-helix bundle including a pierced lasso topology. The conformational dynamics, determined on several timescales, show that leptin is monomeric, has a rigid four-helix scaffold, and a dynamic domain, including a transiently formed helix. The dynamic domain is anchored to the helical scaffold by a secondary hydrophobic core, pinning down the long loops of leptin to the protein body, inducing motional restriction without a well-defined secondary or tertiary hydrogen bond stabilized structure. This dynamic region is well suited for and may be involved in functional allosteric dynamics upon receptor binding.
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http://dx.doi.org/10.1016/j.jmb.2020.01.035DOI Listing
April 2020

Long-term impacts of the CARE program on teachers' self-reported social and emotional competence and well-being.

J Sch Psychol 2019 Oct 26;76:186-202. Epub 2019 Oct 26.

Pennsylvania State University, USA. Electronic address:

Teacher stress is at an all-time high, negatively impacting the quality of education and student outcomes. In recent years, mindfulness-based interventions have been shown to promote well-being and reduce stress among healthy adults. In particular, mindfulness-based interventions enhance emotion regulation and reduce psychological distress. One such program specifically designed to address teacher stress is Cultivating Awareness and Resilience in Education (CARE). The present study examined teachers' self-reported data collected at three time points over two consecutive school years as part of a randomized controlled trial of CARE. The study involved 224 teachers in 36 elementary schools in high poverty areas of New York City. Teachers were randomly assigned within schools to receive CARE or to a waitlist control group. This study builds on previous experimental evidence of the impacts of CARE on teacher self-reported outcomes for this sample of teachers within one school year (Jennings et al., 2017). Results indicate that at the third assessment point (9.5 months after participating in the program), CARE teachers showed continued significant decreases in psychological distress, reductions in ache-related physical distress, continued significant increases in emotion regulation and some dimensions of mindfulness. Findings indicate that teachers who participated in mindfulness-based professional development through CARE reported both sustained and new benefits regarding their well-being at a follow-up assessment almost one-year post-intervention compared to teachers in the control condition. Implications for further research and policy are discussed.
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http://dx.doi.org/10.1016/j.jsp.2019.07.009DOI Listing
October 2019

Redox-dependent gating of VDAC by mitoNEET.

Proc Natl Acad Sci U S A 2019 10 16;116(40):19924-19929. Epub 2019 Sep 16.

Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093-0375;

MitoNEET is an outer mitochondrial membrane protein essential for sensing and regulation of iron and reactive oxygen species (ROS) homeostasis. It is a key player in multiple human maladies including diabetes, cancer, neurodegeneration, and Parkinson's diseases. In healthy cells, mitoNEET receives its clusters from the mitochondrion and transfers them to acceptor proteins in a process that could be altered by drugs or during illness. Here, we report that mitoNEET regulates the outer-mitochondrial membrane (OMM) protein voltage-dependent anion channel 1 (VDAC1). VDAC1 is a crucial player in the cross talk between the mitochondria and the cytosol. VDAC proteins function to regulate metabolites, ions, ROS, and fatty acid transport, as well as function as a "governator" sentry for the transport of metabolites and ions between the cytosol and the mitochondria. We find that the redox-sensitive [2Fe-2S] cluster protein mitoNEET gates VDAC1 when mitoNEET is oxidized. Addition of the VDAC inhibitor 4,4'-diisothiocyanatostilbene-2,2'-disulfonate (DIDS) prevents both mitoNEET binding in vitro and mitoNEET-dependent mitochondrial iron accumulation in situ. We find that the DIDS inhibitor does not alter the redox state of MitoNEET. Taken together, our data indicate that mitoNEET regulates VDAC in a redox-dependent manner in cells, closing the pore and likely disrupting VDAC's flow of metabolites.
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http://dx.doi.org/10.1073/pnas.1908271116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778226PMC
October 2019

The Effect of Teacher-Child Race/Ethnicity Matching and Classroom Diversity on Children's Socioemotional and Academic Skills.

Child Dev 2020 05 23;91(3):e597-e618. Epub 2019 Jun 23.

University of Virginia.

Mounting evidence suggests teacher-child race/ethnicity matching and classroom diversity benefit Black and Latinx children's academic and socioemotional development. However, less is known about whether the effects of teacher-child matching differ across levels of classroom diversity. This study examined effects of matching on teacher-reported child outcomes in a racially/ethnically diverse sample of teachers and children, and classroom diversity moderation using multilevel models. Data were drawn from a professional learning study involving 224 teachers (M  = 41.5) and 5,200 children (M  = 7.7) in 36 New York City elementary schools. Teacher-child race/ethnicity matching was associated with higher child engagement in learning, motivation, social skills, and fewer absences. Classroom diversity moderated matching such that teacher-child mismatch was related to lower engagement, motivation, social skills, math and reading scores in low-diversity classrooms, but not in high-diversity classrooms. Implications for practice and policy are discussed.
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http://dx.doi.org/10.1111/cdev.13275DOI Listing
May 2020

Cigarette Smoke Triggers IL-33-associated Inflammation in a Model of Late-Stage Chronic Obstructive Pulmonary Disease.

Am J Respir Cell Mol Biol 2019 11;61(5):567-574

Department of Medicine and.

Chronic obstructive pulmonary disease (COPD) is a worldwide threat. Cigarette smoke (CS) exposure causes cardiopulmonary disease and COPD and increases the risk for pulmonary tumors. In addition to poor lung function, patients with COPD are susceptible to bouts of dangerous inflammation triggered by pollutants or infection. These severe inflammatory episodes can lead to additional exacerbations, hospitalization, further deterioration of lung function, and reduced survival. Suitable models of the inflammatory conditions associated with CS, which potentiate the downward spiral in patients with COPD, are lacking, and the underlying mechanisms that trigger exacerbations are not well understood. Although initial CS exposure activates a protective role for vascular endothelial growth factor (VEGF) functions in barrier integrity, chronic exposure depletes the pulmonary VEGF guard function in severe COPD. Thus, we hypothesized that mice with compromised VEGF production and challenged with CS would trigger human-like severe inflammatory progression of COPD. In this model, we discovered that CS exposure promotes an amplified IL-33 cytokine response and severe disease progression. Our -knockout model combined with CS recapitulates severe COPD with an influx of IL-33-expressing macrophages and neutrophils. Normally, IL-33 is quickly inactivated by a post-translational disulfide bond formation. Our results reveal that BAL fluid from the CS-exposed, VEGF-deficient cohort promotes a significantly prolonged lifetime of active proinflammatory IL-33. Taken together, our data demonstrate that with the loss of a VEGF-mediated protective barrier, the CS response switches from a localized danger to an uncontrolled long-term and long-range, amplified, IL-33-mediated inflammatory response that ultimately destroys lung function.
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http://dx.doi.org/10.1165/rcmb.2018-0402OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827064PMC
November 2019

The anti-apoptotic proteins NAF-1 and iASPP interact to drive apoptosis in cancer cells.

Chem Sci 2019 Jan 20;10(3):665-673. Epub 2018 Nov 20.

The Alexander Silberman Institute of Life Science , The Hebrew University of Jerusalem , Edmond J. Safra Campus at Givat Ram , Jerusalem 91904 , Israel . Email:

Suppression of apoptosis is a key Hallmark of cancer cells, and reactivation of apoptosis is a major avenue for cancer therapy. We reveal an interaction between the two anti-apoptotic proteins iASPP and NAF-1, which are overexpressed in many types of cancer cells and tumors. iASPP is an inhibitory member of the ASPP protein family, whereas NAF-1 belongs to the NEET 2Fe-2S protein family. We show that the two proteins are stimulated to interact in cells during apoptosis. Using peptide array screening and computational methods we mapped the interaction interfaces of both proteins to residues 764-778 of iASPP that bind to a surface groove of NAF-1. A peptide corresponding to the iASPP 764-780 sequence stabilized the NAF-1 cluster, inhibited NAF-1 interaction with iASPP, and inhibited staurosporine-induced apoptosis activation in human breast cancer, as well as in PC-3 prostate cancer cells in which p53 is inactive. The iASPP 764-780 IC value for inhibition of cell death in breast cancer cells was 13 ± 1 μM. The level of cell death inhibition by iASPP 764-780 was altered in breast cancer cells expressing different levels and/or variants of NAF-1, indicating that the peptide activity is associated with NAF-1 function. We propose that the interaction between iASPP and NAF-1 is required for apoptosis activation in cancer cells. This interaction uncovers a new layer in the highly complex regulation of cell death in cancer cells and opens new avenues of exploration into the development of novel anticancer drugs that reactivate apoptosis in malignant tumors.
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http://dx.doi.org/10.1039/c8sc03390kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349067PMC
January 2019

Contemplative neuroscience, self-awareness, and education.

Prog Brain Res 2019 3;244:355-385. Epub 2019 Jan 3.

Faculty of Education, University of Haifa, Haifa, Israel.

Accumulating research in education shows that contemplative practices contribute to and foster well-being of individuals in sustainable ways. This bears special importance for teachers, as it affects not only them but also their students. Based on accumulating behavioral and neuroscientific findings, it has been suggested that a key process by which mindfulness meditation enhances self-regulation is the altering of self-awareness. Indeed, accumulated work shows that the underlying networks supporting various types of self-awareness are malleable following meditative practice. However, the field of education has developed independently from the study of the self and its relation to contemplative neuroscience thus far, and to date there is no systematic account linking this accumulating body of knowledge to the field of education or discussing how it might be relevant to teachers. Here we show how incorporating insights from contemplative neuroscience-which are built on the conceptualization and neuroscience of the self-into contemplative pedagogy can inform the field and might even serve as a core underlying mechanism tying together different empirical evidence. This review points to potential neural mechanisms by which mindfulness meditation helps teachers manage stress and promote supportive learning environments, resulting in improved educational outcomes, and thus it has significant implications for educational policy regarding teachers.
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http://dx.doi.org/10.1016/bs.pbr.2018.10.015DOI Listing
April 2019

Designing bacterial signaling interactions with coevolutionary landscapes.

PLoS One 2018 20;13(8):e0201734. Epub 2018 Aug 20.

Center for Theoretical Biological Physics, Rice University, Houston, Texas, United States of America.

Selecting amino acids to design novel protein-protein interactions that facilitate catalysis is a daunting challenge. We propose that a computational coevolutionary landscape based on sequence analysis alone offers a major advantage over expensive, time-consuming brute-force approaches currently employed. Our coevolutionary landscape allows prediction of single amino acid substitutions that produce functional interactions between non-cognate, interspecies signaling partners. In addition, it can also predict mutations that maintain segregation of signaling pathways across species. Specifically, predictions of phosphotransfer activity between the Escherichia coli histidine kinase EnvZ to the non-cognate receiver Spo0F from Bacillus subtilis were compiled. Twelve mutations designed to enhance, suppress, or have a neutral effect on kinase phosphotransfer activity to a non-cognate partner were selected. We experimentally tested the ability of the kinase to relay phosphate to the respective designed Spo0F receiver proteins against the theoretical predictions. Our key finding is that the coevolutionary landscape theory, with limited structural data, can significantly reduce the search-space for successful prediction of single amino acid substitutions that modulate phosphotransfer between the two-component His-Asp relay partners in a predicted fashion. This combined approach offers significant improvements over large-scale mutations studies currently used for protein engineering and design.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201734PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6101370PMC
February 2019

Uncovering the molecular mechanisms behind disease-associated leptin variants.

J Biol Chem 2018 08 27;293(33):12919-12933. Epub 2018 Jun 27.

Center for Theoretical Biological Physics, and Biosciences, Rice University, Houston, Texas 77005; Departments of Physics and Astronomy, Chemistry, and Biosciences, Rice University, Houston, Texas 77005. Electronic address:

The pleiotropic hormone leptin has a pivotal role in regulating energy balance by inhibiting hunger and increasing energy expenditure. Homozygous mutations found in the leptin gene are associated with extreme obesity, marked hyperphagia, and impaired immune function. Although these mutations have been characterized , a detailed understanding of how they affect leptin structure and function remains elusive. In the current work, we used NMR, differential scanning calorimetry, molecular dynamics simulations, and bioinformatics calculations to characterize the effects of these mutations on leptin structure and function and binding to its cognate receptor. We found that mutations identified in patients with congenital leptin deficiency not only cause leptin misfolding or aggregation, but also cause changes in the dynamics of leptin residues on the receptor-binding interface. Therefore, we infer that mutation-induced leptin deficiency may arise from several distinct mechanisms including (i) blockade of leptin receptor interface II, (ii) decreased affinity in the second step of leptin's interaction with its receptor, (iii) leptin destabilization, and (iv) unsuccessful threading through the covalent loop, leading to leptin misfolding/aggregation. We propose that this expanded framework for understanding the mechanisms underlying leptin deficiency arising from genetic mutations may be useful in designing therapeutics for leptin-associated disorders.
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http://dx.doi.org/10.1074/jbc.RA118.003957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102133PMC
August 2018

Broad-Spectrum Regulation of Nonreceptor Tyrosine Kinases by the Bacterial ADP-Ribosyltransferase EspJ.

mBio 2018 04 10;9(2). Epub 2018 Apr 10.

Centre for Molecular Microbiology and Infection, Department of Life Sciences, Imperial College, London United Kingdom, London, United Kingdom

Tyrosine phosphorylation is key for signal transduction from exogenous stimuli, including the defense against pathogens. Conversely, pathogens can subvert protein phosphorylation to control host immune responses and facilitate invasion and dissemination. The bacterial effectors EspJ and SeoC are injected into host cells through a type III secretion system by enteropathogenic and enterohemorrhagic (EPEC and EHEC, respectively), , and , where they inhibit Src kinase by coupled amidation and ADP-ribosylation. , which is used to model EPEC and EHEC infections in humans, is a mouse pathogen triggering colonic crypt hyperplasia (CCH) and colitis. Enumeration of bacterial shedding and CCH confirmed that EspJ affects neither tolerance nor resistance to infection. However, comparison of the proteomes of intestinal epithelial cells isolated from mice infected with wild-type or encoding catalytically inactive EspJ revealed that EspJ-induced ADP-ribosylation regulates multiple nonreceptor tyrosine kinases Investigation of the substrate repertoire of EspJ revealed that in HeLa and A549 cells, Src and Csk were significantly targeted; in polarized Caco2 cells, EspJ targeted Src and Csk and the Src family kinase (SFK) Yes1, while in differentiated Thp1 cells, EspJ modified Csk, the SFKs Hck and Lyn, the Tec family kinases Tec and Btk, and the adapter tyrosine kinase Syk. Furthermore, Abl (HeLa and Caco2) and Lyn (Caco2) were enriched specifically in the EspJ-containing samples. Biochemical assays revealed that EspJ, the only bacterial ADP-ribosyltransferase that targets mammalian kinases, controls immune responses and the Src/Csk signaling axis. Enteropathogenic and enterohemorrhagic (EPEC and EHEC, respectively) strains cause significant mortality and morbidity worldwide. is a mouse pathogen used to model EPEC and EHEC pathogenesis Diarrheal disease is triggered following injection of bacterial effectors, via a type III secretion system (T3SS), into intestinal epithelial cells (IECs). While insights into the role of the effectors were historically obtained from pathological, immunologic, or cell culture phenotypes, subtle roles of individual effectors are often masked. The aim of this study was to elucidate the role and specificity of the ADP-ribosyltransferase effector EspJ. For the first time, we show that the processes affected by a T3SS effector can be studied by comparing the proteomes of IECs extracted from mice infected with wild-type or an catalytic mutant. We show that EspJ, the only bacterial ADP-ribosyltransferase that targets mammalian kinases, regulates the host immune response .
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http://dx.doi.org/10.1128/mBio.00170-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893879PMC
April 2018

Phylogenetic analysis of the CDGSH iron-sulfur binding domain reveals its ancient origin.

Sci Rep 2018 03 19;8(1):4840. Epub 2018 Mar 19.

Department of Biological Sciences, University of North Texas, Denton, TX, 76203, USA.

The iron-sulfur (2Fe-2S) binding motif CDGSH appears in many important plant and animal proteins that regulate iron and reactive oxygen metabolism. In human it is found in CISD1-3 proteins involved in diabetes, obesity, cancer, aging, cardiovascular disease and neurodegeneration. Despite the important biological role of the CDGSH domain, its origin, evolution and diversification, are largely unknown. Here, we report that: (1) the CDGSH domain appeared early in evolution, perhaps linked to the heavy use of iron-sulfur driven metabolism by early organisms; (2) a CISD3-like protein with two CDGSH domains on the same polypeptide appears to represent the ancient archetype of CDGSH proteins; (3) the origin of the human CISD3 protein is linked to the mitochondrial endosymbiotic event; (4) the CISD1/2 type proteins that contain only one CDGSH domain, but function as homodimers, originated after the divergence of bacteria and archaea/eukaryotes from their common ancestor; and (5) the human CISD1 and CISD2 proteins diverged about 650-720 million years ago, and CISD3 and CISD1/2 share their descent from an ancestral CISD about 1-1.1 billion years ago. Our findings reveal that the CDGSH domain is ancient in its origin and shed light on the complex evolutionary path of modern CDGSH proteins.
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http://dx.doi.org/10.1038/s41598-018-23305-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859297PMC
March 2018

NEET Proteins: A New Link Between Iron Metabolism, Reactive Oxygen Species, and Cancer.

Antioxid Redox Signal 2019 03 29;30(8):1083-1095. Epub 2018 Mar 29.

2 The Alexander Silberman Institute of Life Science, The Wolfson Institute for Applied Structural Biology, Hebrew University of Jerusalem , Jerusalem, Israel .

Significance: Cancer cells accumulate high levels of iron and reactive oxygen species (ROS) to promote their high metabolic activity and proliferation rate. However, high levels of iron and ROS can also lead to enhanced oxidative stress and the activation of cell death pathways such as apoptosis and ferroptosis. This has led to the proposal that different drugs that target iron and/or ROS metabolism could be used as anticancer drugs. However, due to the complex role iron and ROS play in cells, the majority of these drugs yielded mixed results, highlighting a critical need to identify new players in the regulation of iron and ROS homeostasis in cancer cells. Recent Advances: NEET proteins belong to a newly discovered class of iron-sulfur proteins (2Fe-2S) required for the regulation of iron and ROS homeostasis in cells. Recent studies revealed that the NEET proteins NAF-1 (CISD2) and mitoNEET (CISD1) play a critical role in promoting the proliferation of cancer cells, supporting tumor growth and metastasis. Moreover, the function of NEET proteins in cancer cells was found to be dependent of the degree of lability of their 2Fe-2S clusters.

Critical Issues: NEET proteins could represent a key regulatory link between the maintenance of high iron and ROS in cancer cells, the activation of cell death and survival pathways, and cellular proliferation.

Future Directions: Because the function of NEET proteins depends on the lability of their clusters, drugs that target the 2Fe2S clusters of NEET proteins could be used as promising anticancer drugs.
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http://dx.doi.org/10.1089/ars.2018.7502DOI Listing
March 2019

The unique fold and lability of the [2Fe-2S] clusters of NEET proteins mediate their key functions in health and disease.

J Biol Inorg Chem 2018 06 12;23(4):599-612. Epub 2018 Feb 12.

The Alexander Silberman Life Science Institute and the Wolfson Center for Applied Structural Biology, The Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, 91904-0375, Jerusalem, Israel.

NEET proteins comprise a new class of [2Fe-2S] cluster proteins. In human, three genes encode for NEET proteins: cisd1 encodes mitoNEET (mNT), cisd2 encodes the Nutrient-deprivation autophagy factor-1 (NAF-1) and cisd3 encodes MiNT (Miner2). These recently discovered proteins play key roles in many processes related to normal metabolism and disease. Indeed, NEET proteins are involved in iron, Fe-S, and reactive oxygen homeostasis in cells and play an important role in regulating apoptosis and autophagy. mNT and NAF-1 are homodimeric and reside on the outer mitochondrial membrane. NAF-1 also resides in the membranes of the ER associated mitochondrial membranes (MAM) and the ER. MiNT is a monomer with distinct asymmetry in the molecular surfaces surrounding the clusters. Unlike its paralogs mNT and NAF-1, it resides within the mitochondria. NAF-1 and mNT share similar backbone folds to the plant homodimeric NEET protein (At-NEET), while MiNT's backbone fold resembles a bacterial MiNT protein. Despite the variation of amino acid composition among these proteins, all NEET proteins retained their unique CDGSH domain harboring their unique 3Cys:1His [2Fe-2S] cluster coordination through evolution. The coordinating exposed His was shown to convey the lability to the NEET proteins' [2Fe-2S] clusters. In this minireview, we discuss the NEET fold and its structural elements. Special attention is given to the unique lability of the NEETs' [2Fe-2S] cluster and the implication of the latter to the NEET proteins' cellular and systemic function in health and disease.
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http://dx.doi.org/10.1007/s00775-018-1538-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006223PMC
June 2018

Structure of the human monomeric NEET protein MiNT and its role in regulating iron and reactive oxygen species in cancer cells.

Proc Natl Acad Sci U S A 2018 01 19;115(2):272-277. Epub 2017 Dec 19.

Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093;

The NEET family is a relatively new class of three related [2Fe-2S] proteins (CISD1-3), important in human health and disease. While there has been growing interest in the homodimeric gene products of CISD1 (mitoNEET) and CISD2 (NAF-1), the importance of the inner mitochondrial CISD3 protein has only recently been recognized in cancer. The CISD3 gene encodes for a monomeric protein that contains two [2Fe-2S] CDGSH motifs, which we term mitochondrial inner NEET protein (MiNT). It folds with a pseudosymmetrical fold that provides a hydrophobic motif on one side and a relatively hydrophilic surface on the diametrically opposed surface. Interestingly, as shown by molecular dynamics simulation, the protein displays distinct asymmetrical backbone motions, unlike its homodimeric counterparts that face the cytosolic side of the outer mitochondrial membrane/endoplasmic reticulum (ER). However, like its counterparts, our biological studies indicate that knockdown of MiNT leads to increased accumulation of mitochondrial labile iron, as well as increased mitochondrial reactive oxygen production. Taken together, our study suggests that the MiNT protein functions in the same pathway as its homodimeric counterparts (mitoNEET and NAF-1), and could be a key player in this pathway within the mitochondria. As such, it represents a target for anticancer or antidiabetic drug development.
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http://dx.doi.org/10.1073/pnas.1715842115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777063PMC
January 2018

Molecular Dynamics Simulations of the [2Fe-2S] Cluster-Binding Domain of NEET Proteins Reveal Key Molecular Determinants That Induce Their Cluster Transfer/Release.

J Phys Chem B 2017 11 16;121(47):10648-10656. Epub 2017 Nov 16.

Computational Biomedicine Section, Institute of Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH , 52425 Jülich, Germany.

The NEET proteins are a novel family of iron-sulfur proteins characterized by an unusual three cysteine and one histidine coordinated [2Fe-2S] cluster. Aberrant cluster release, facilitated by the breakage of the Fe-N bond, is implicated in a variety of human diseases, including cancer. Here, the molecular dynamics in the multi-microsecond timescale, along with quantum chemical calculations, on two representative members of the family (the human NAF-1 and mitoNEET proteins), show that the loss of the cluster is associated with a dramatic decrease in secondary and tertiary structure. In addition, the calculations provide a mechanism for cluster release and clarify, for the first time, crucial differences existing between the two proteins, which are reflected in the experimentally observed difference in the pH-dependent cluster reactivity. The reliability of our conclusions is established by an extensive comparison with the NMR data of the solution proteins, in part measured in this work.
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http://dx.doi.org/10.1021/acs.jpcb.7b10584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5713697PMC
November 2017

Educators' emotion regulation strategies and their physiological indicators of chronic stress over 1 year.

Stress Health 2018 Apr 9;34(2):278-285. Epub 2017 Oct 9.

Curry School of Education, University of Virginia, Charlottesville, VA, USA.

Studies show teaching is a highly stressful profession and that chronic work stress is associated with adverse health outcomes. This study analysed physiological markers of stress and self-reported emotion regulation strategies in a group of middle school teachers over 1 year. Chronic physiological stress was assessed with diurnal cortisol measures at three time points over 1 year (fall, spring, fall). The aim of this longitudinal study was to investigate the changes in educators' physiological level of stress. Results indicate that compared to those in the fall, cortisol awakening responses were blunted in the spring. Further, this effect was ameliorated by the summer break. Additionally, self-reported use of the emotion regulation strategy reappraisal buffered the observed blunting that occurred in the spring.
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http://dx.doi.org/10.1002/smi.2782DOI Listing
April 2018

Redirecting SR Protein Nuclear Trafficking through an Allosteric Platform.

J Mol Biol 2017 07 31;429(14):2178-2191. Epub 2017 May 31.

Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0636, USA. Electronic address:

Although phosphorylation directs serine-arginine (SR) proteins from nuclear storage speckles to the nucleoplasm for splicing function, dephosphorylation paradoxically induces similar movement, raising the question of how such chemical modifications are balanced in these essential splicing factors. In this new study, we investigated the interaction of protein phosphatase 1 (PP1) with the SR protein splicing factor (SRSF1) to understand the foundation of these opposing effects in the nucleus. We found that RNA recognition motif 1 (RRM1) in SRSF1 binds PP1 and represses its catalytic function through an allosteric mechanism. Disruption of RRM1-PP1 interactions reduces the phosphorylation status of the RS domain in vitro and in cells, redirecting SRSF1 in the nucleus. The data imply that an allosteric SR protein-phosphatase platform balances phosphorylation levels in a "goldilocks" region for the proper subnuclear storage of an SR protein splicing factor.
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http://dx.doi.org/10.1016/j.jmb.2017.05.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536852PMC
July 2017

Interactions between mitoNEET and NAF-1 in cells.

PLoS One 2017 20;12(4):e0175796. Epub 2017 Apr 20.

Department of Biological Sciences and BioDiscovery Institute, University of North Texas, Denton, Texas, United States of America.

The NEET proteins mitoNEET (mNT) and nutrient-deprivation autophagy factor-1 (NAF-1) are required for cancer cell proliferation and resistance to oxidative stress. NAF-1 and mNT are also implicated in a number of other human pathologies including diabetes, neurodegeneration and cardiovascular disease, as well as in development, differentiation and aging. Previous studies suggested that mNT and NAF-1 could function in the same pathway in mammalian cells, preventing the over-accumulation of iron and reactive oxygen species (ROS) in mitochondria. Nevertheless, it is unknown whether these two proteins directly interact in cells, and how they mediate their function. Here we demonstrate, using yeast two-hybrid, in vivo bimolecular fluorescence complementation (BiFC), direct coupling analysis (DCA), RNA-sequencing, ROS and iron imaging, and single and double shRNA lines with suppressed mNT, NAF-1 and mNT/NAF-1 expression, that mNT and NAF-1 directly interact in mammalian cells and could function in the same cellular pathway. We further show using an in vitro cluster transfer assay that mNT can transfer its clusters to NAF-1. Our study highlights the possibility that mNT and NAF-1 function as part of an iron-sulfur (2Fe-2S) cluster relay to maintain the levels of iron and Fe-S clusters under control in the mitochondria of mammalian cells, thereby preventing the activation of apoptosis and/or autophagy and supporting cellular proliferation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175796PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398536PMC
September 2017

Backbone assignments for the SPOUT methyltransferase MTT , a knotted protein from Thermotoga maritima.

Biomol NMR Assign 2017 Oct 10;11(2):151-154. Epub 2017 Mar 10.

Department of Chemistry and Biochemistry, University of California at San Diego (UCSD), La Jolla, CA, USA.

The SPOUT family of methyltransferase proteins is noted for containing a deep trefoil knot in their defining backbone fold. This unique fold is of high interest for furthering the understanding of knots in proteins. Here, we report the H, C, N assignments for MTT , a canonical member of the SPOUT family. This protein is unique, as it is one of the smallest members of the family, making it an ideal system for probing the unique properties of the knot. Our present work represents the foundation for further studies into the topology of MTT , and understanding how its structure affects both its folding and function.
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http://dx.doi.org/10.1007/s12104-017-9737-8DOI Listing
October 2017

Phylogenetic analysis of eukaryotic NEET proteins uncovers a link between a key gene duplication event and the evolution of vertebrates.

Sci Rep 2017 02 16;7:42571. Epub 2017 Feb 16.

Department of Biological Sciences, University of North Texas, Denton TX 76203, USA.

NEET proteins belong to a unique family of iron-sulfur proteins in which the 2Fe-2S cluster is coordinated by a CDGSH domain that is followed by the "NEET" motif. They are involved in the regulation of iron and reactive oxygen metabolism, and have been associated with the progression of diabetes, cancer, aging and neurodegenerative diseases. Despite their important biological functions, the evolution and diversification of eukaryotic NEET proteins are largely unknown. Here we used the three members of the human NEET protein family (CISD1, mitoNEET; CISD2, NAF-1 or Miner 1; and CISD3, Miner2) as our guides to conduct a phylogenetic analysis of eukaryotic NEET proteins and their evolution. Our findings identified the slime mold Dictyostelium discoideum's CISD proteins as the closest to the ancient archetype of eukaryotic NEET proteins. We further identified CISD3 homologs in fungi that were previously reported not to contain any NEET proteins, and revealed that plants lack homolog(s) of CISD3. Furthermore, our study suggests that the mammalian NEET proteins, mitoNEET (CISD1) and NAF-1 (CISD2), emerged via gene duplication around the origin of vertebrates. Our findings provide new insights into the classification and expansion of the NEET protein family, as well as offer clues to the diverged functions of the human mitoNEET and NAF-1 proteins.
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http://dx.doi.org/10.1038/srep42571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5311916PMC
February 2017

Pierced Lasso Topology Controls Function in Leptin.

J Phys Chem B 2017 02 18;121(4):706-718. Epub 2017 Jan 18.

Center for Theoretical Biological Physics (CTBP) and Departments of Physics and Astronomy, Chemistry and Biosciences, Rice University , Houston, Texas, United States.

Protein engineering is a powerful tool in drug design and therapeutics, where disulphide bridges are commonly introduced to stabilize proteins. However, these bonds also introduce covalent loops, which are often neglected. These loops may entrap the protein backbone on opposite sides, leading to a "knotted" topology, forming a so-called Pierced Lasso (PL). In this elegant system, the "knot" is held together with a single disulphide bridge where part of the polypeptide chain is threaded through. The size and position of these covalent loops can be manipulated through protein design in vitro, whereas nature uses polymorphism to switch the PL topology. The PL protein leptin shows genetic modification of an N-terminal residue, adding a third cysteine to the same sequence. In an effort to understand the mechanism of threading of these diverse topologies, we designed three loop variants to mimic the polymorphic sequence. This adds elegance to the system under study, as it allows the generation of three possible covalent loops; they are the original wild-type C-terminal loop protein, the fully circularized unthreaded protein, and the N-terminal loop protein, responsible for different lasso topologies. The size of the loop changes the threading mechanism from a slipknotting to a plugging mechanism, with increasing loop size. Interestingly, the ground state of the native protein structure is largely unaffected, but biological assays show that the activity is maximized by properly controlled dynamics in the threaded state. A threaded topology with proper conformational dynamics is important for receptor interaction and activation of the signaling pathways in vivo.
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http://dx.doi.org/10.1021/acs.jpcb.6b11506DOI Listing
February 2017

Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters.

Proc Natl Acad Sci U S A 2016 09 12;113(39):10890-5. Epub 2016 Sep 12.

The Alexander Silberman Institute of Life Science, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel;

Iron-sulfur (Fe-S) proteins are thought to play an important role in cancer cells mediating redox reactions, DNA replication, and telomere maintenance. Nutrient-deprivation autophagy factor-1 (NAF-1) is a 2Fe-2S protein associated with the progression of multiple cancer types. It is unique among Fe-S proteins because of its 3Cys-1His cluster coordination structure that allows it to be relatively stable, as well as to transfer its clusters to apo-acceptor proteins. Here, we report that overexpression of NAF-1 in xenograft breast cancer tumors results in a dramatic augmentation in tumor size and aggressiveness and that NAF-1 overexpression enhances the tolerance of cancer cells to oxidative stress. Remarkably, overexpression of a NAF-1 mutant with a single point mutation that stabilizes the NAF-1 cluster, NAF-1(H114C), in xenograft breast cancer tumors results in a dramatic decrease in tumor size that is accompanied by enhanced mitochondrial iron and reactive oxygen accumulation and reduced cellular tolerance to oxidative stress. Furthermore, treating breast cancer cells with pioglitazone that stabilizes the 3Cys-1His cluster of NAF-1 results in a similar effect on mitochondrial iron and reactive oxygen species accumulation. Taken together, our findings point to a key role for the unique 3Cys-1His cluster of NAF-1 in promoting rapid tumor growth through cellular resistance to oxidative stress. Cluster transfer reactions mediated by the overexpressed NAF-1 protein are therefore critical for inducing oxidative stress tolerance in cancer cells, leading to rapid tumor growth, and drugs that stabilize the NAF-1 cluster could be used as part of a treatment strategy for cancers that display high NAF-1 expression.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5047192PMC
http://dx.doi.org/10.1073/pnas.1612736113DOI Listing
September 2016

Gambogic acid identifies an isoform-specific druggable pocket in the middle domain of Hsp90β.

Proc Natl Acad Sci U S A 2016 08 27;113(33):E4801-9. Epub 2016 Jul 27.

Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

Because of their importance in maintaining protein homeostasis, molecular chaperones, including heat-shock protein 90 (Hsp90), represent attractive drug targets. Although a number of Hsp90 inhibitors are in preclinical/clinical development, none strongly differentiate between constitutively expressed Hsp90β and stress-induced Hsp90α, the two cytosolic paralogs of this molecular chaperone. Thus, the importance of inhibiting one or the other paralog in different disease states remains unknown. We show that the natural product, gambogic acid (GBA), binds selectively to a site in the middle domain of Hsp90β, identifying GBA as an Hsp90β-specific Hsp90 inhibitor. Furthermore, using computational and medicinal chemistry, we identified a GBA analog, referred to as DAP-19, which binds potently and selectively to Hsp90β. Because of its unprecedented selectivity for Hsp90β among all Hsp90 paralogs, GBA thus provides a new chemical tool to study the unique biological role of this abundantly expressed molecular chaperone in health and disease.
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http://dx.doi.org/10.1073/pnas.1606655113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995996PMC
August 2016

Untangling the Influence of a Protein Knot on Folding.

Biophys J 2016 Mar;110(5):1044-51

Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California. Electronic address:

Entanglement and knots occur across all aspects of the physical world. Despite the common belief that knots are too complicated for incorporation into proteins, knots have been identified in the native fold of a growing number of proteins. The discovery of proteins with this unique backbone characteristic has challenged the preconceptions about the complexity of biological structures, as well as current folding theories. Given the intricacies of the knotted geometry, the interplay between a protein's fold, structure, and function is of particular interest. Interestingly, for most of these proteins, the knotted region appears critical both in folding and function, although full understanding of these contributions is still incomplete. Here, we experimentally reveal the impact of the knot on the landscape, the origin of the bistable nature of the knotted protein, and broaden the view of knot formation as uniquely decoupled from folding.
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http://dx.doi.org/10.1016/j.bpj.2016.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788744PMC
March 2016

Geometrical Frustration in Interleukin-33 Decouples the Dynamics of the Functional Element from the Folding Transition State Ensemble.

PLoS One 2015 2;10(12):e0144067. Epub 2015 Dec 2.

Department of Chemistry and Biochemistry, University of California at San Diego (UCSD), La Jolla, CA, United States of America.

Interleukin-33 (IL-33) is currently the focus of multiple investigations into targeting pernicious inflammatory disorders. This mediator of inflammation plays a prevalent role in chronic disorders such as asthma, rheumatoid arthritis, and progressive heart disease. In order to better understand the possible link between the folding free energy landscape and functional regions in IL-33, a combined experimental and theoretical approach was applied. IL-33 is a pseudo- symmetrical protein composed of three distinct structural elements that complicate the folding mechanism due to competition for nucleation on the dominant folding route. Trefoil 1 constitutes the majority of the binding interface with the receptor whereas Trefoils 2 and 3 provide the stable scaffold to anchor Trefoil 1. We identified that IL-33 folds with a three-state mechanism, leading to a rollover in the refolding arm of its chevron plots in strongly native conditions. In addition, there is a second slower refolding phase that exhibits the same rollover suggesting similar limitations in folding along parallel routes. Characterization of the intermediate state and the rate limiting steps required for folding suggests that the rollover is attributable to a moving transition state, shifting from a post- to pre-intermediate transition state as you move from strongly native conditions to the midpoint of the transition. On a structural level, we found that initially, all independent Trefoil units fold equally well until a QCA of 0.35 when Trefoil 1 will backtrack in order to allow Trefoils 2 and 3 to fold in the intermediate state, creating a stable scaffold for Trefoil 1 to fold onto during the final folding transition. The formation of this intermediate state and subsequent moving transition state is a result of balancing the difficulty in folding the functionally important Trefoil 1 onto the remainder of the protein. Taken together our results indicate that the functional element of the protein is geometrically frustrated, requiring the more stable elements to fold first, acting as a scaffold for docking of the functional element to allow productive folding to the native state.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0144067PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667907PMC
June 2016

Activation of apoptosis in NAF-1-deficient human epithelial breast cancer cells.

J Cell Sci 2016 Jan 30;129(1):155-65. Epub 2015 Nov 30.

Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA

Maintaining iron (Fe) ion and reactive oxygen species homeostasis is essential for cellular function, mitochondrial integrity and the regulation of cell death pathways, and is recognized as a key process underlying the molecular basis of aging and various diseases, such as diabetes, neurodegenerative diseases and cancer. Nutrient-deprivation autophagy factor 1 (NAF-1; also known as CISD2) belongs to a newly discovered class of Fe-sulfur proteins that are localized to the outer mitochondrial membrane and the endoplasmic reticulum. It has been implicated in regulating homeostasis of Fe ions, as well as the activation of autophagy through interaction with BCL-2. Here we show that small hairpin (sh)RNA-mediated suppression of NAF-1 results in the activation of apoptosis in epithelial breast cancer cells and xenograft tumors. Suppression of NAF-1 resulted in increased uptake of Fe ions into cells, a metabolic shift that rendered cells more susceptible to a glycolysis inhibitor, and the activation of cellular stress pathways that are associated with HIF1α. Our studies suggest that NAF-1 is a major player in the metabolic regulation of breast cancer cells through its effects on cellular Fe ion distribution, mitochondrial metabolism and the induction of apoptosis.
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http://dx.doi.org/10.1242/jcs.178293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4732299PMC
January 2016

Cancer-Related NEET Proteins Transfer 2Fe-2S Clusters to Anamorsin, a Protein Required for Cytosolic Iron-Sulfur Cluster Biogenesis.

PLoS One 2015 8;10(10):e0139699. Epub 2015 Oct 8.

Departments of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, 92093, United States of America.

Iron-sulfur cluster biogenesis is executed by distinct protein assembly systems. Mammals have two systems, the mitochondrial Fe-S cluster assembly system (ISC) and the cytosolic assembly system (CIA), that are connected by an unknown mechanism. The human members of the NEET family of 2Fe-2S proteins, nutrient-deprivation autophagy factor-1 (NAF-1) and mitoNEET (mNT), are located at the interface between the mitochondria and the cytosol. These proteins have been implicated in cancer cell proliferation, and they can transfer their 2Fe-2S clusters to a standard apo-acceptor protein. Here we report the first physiological 2Fe-2S cluster acceptor for both NEET proteins as human Anamorsin (also known as cytokine induced apoptosis inhibitor-1; CIAPIN-1). Anamorsin is an electron transfer protein containing two iron-sulfur cluster-binding sites that is required for cytosolic Fe-S cluster assembly. We show, using UV-Vis spectroscopy, that both NAF-1 and mNT can transfer their 2Fe-2S clusters to apo-Anamorsin with second order rate constants similar to those of other known human 2Fe-2S transfer proteins. A direct protein-protein interaction of the NEET proteins with apo-Anamorsin was detected using biolayer interferometry. Furthermore, electrospray mass spectrometry of holo-Anamorsin prepared by cluster transfer shows that it receives both of its 2Fe-2S clusters from the NEETs. We propose that mNT and NAF-1 can provide parallel routes connecting the mitochondrial ISC system and the CIA. 2Fe-2S clusters assembled in the mitochondria are received by NEET proteins and when needed transferred to Anamorsin, activating the CIA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0139699PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4598119PMC
June 2016