Publications by authors named "Jean-Philippe Cartailler"

16 Publications

  • Page 1 of 1

Distinct patterns of clonal evolution drive myelodysplastic syndrome progression to secondary acute myeloid leukemia  .

Blood Cancer Discov 2022 May 6. Epub 2022 May 6.

Vanderbilt University Medical Center, Nashville, TN, United States.

Clonal evolution in myelodysplastic syndrome (MDS) can result in clinical progression and secondary acute myeloid leukemia (sAML). To dissect changes in clonal architecture associated with this progression, we performed single-cell genotyping of paired MDS and sAML samples from 18 patients. Analysis of single-cell genotypes revealed patient-specific clonal evolution and enabled assessment of single-cell mutational co-occurrence. We discovered changes in clonal architecture proceed via distinct patterns, classified as static or dynamic, with dynamic clonal architectures having a more proliferative phenotype by blast count fold change. Proteogenomic analysis of a subset of patients confirmed pathogenic mutations were primarily confined to primitive and mature myeloid cells, though we also identify rare, but present, mutations in lymphocyte subsets. Single-cell transcriptomic analysis of paired sample sets further identified gene sets and signaling pathways involved in two cases of progression. Together, these data define serial changes in the MDS clonal landscape with clinical and therapeutic implications.
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http://dx.doi.org/10.1158/2643-3230.BCD-21-0128DOI Listing
May 2022

Insm1, Neurod1, and Pax6 promote murine pancreatic endocrine cell development through overlapping yet distinct RNA transcription and splicing programs.

G3 (Bethesda) 2021 10;11(11)

Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA.

Insm1, Neurod1, and Pax6 are essential for the formation and function of pancreatic endocrine cells. Here, we report comparative immunohistochemical, transcriptomic, functional enrichment, and RNA splicing analyses of these genes using gene knock-out mice. Quantitative immunohistochemical analysis confirmed that elimination of each of these three factors variably impairs the proliferation, survival, and differentiation of endocrine cells. Transcriptomic analysis revealed that each factor contributes uniquely to the transcriptome although their effects were overlapping. Functional enrichment analysis revealed that genes downregulated by the elimination of Insm1, Neurod1, and Pax6 are commonly involved in mRNA metabolism, chromatin organization, secretion, and cell cycle regulation, and upregulated genes are associated with protein degradation, autophagy, and apoptotic process. Elimination of Insm1, Neurod1, and Pax6 impaired expression of many RNA-binding proteins thereby altering RNA splicing events, including for Syt14 and Snap25, two genes required for insulin secretion. All three factors are necessary for normal splicing of Syt14, and both Insm1 and Pax6 are necessary for the processing of Snap25. Collectively, these data provide new insights into how Insm1, Neurod1, and Pax6 contribute to the formation of functional pancreatic endocrine cells.
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http://dx.doi.org/10.1093/g3journal/jkab303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527475PMC
October 2021

Combinatorial transcription factor profiles predict mature and functional human islet α and β cells.

JCI Insight 2021 09 22;6(18). Epub 2021 Sep 22.

Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Islet-enriched transcription factors (TFs) exert broad control over cellular processes in pancreatic α and β cells, and changes in their expression are associated with developmental state and diabetes. However, the implications of heterogeneity in TF expression across islet cell populations are not well understood. To define this TF heterogeneity and its consequences for cellular function, we profiled more than 40,000 cells from normal human islets by single-cell RNA-Seq and stratified α and β cells based on combinatorial TF expression. Subpopulations of islet cells coexpressing ARX/MAFB (α cells) and MAFA/MAFB (β cells) exhibited greater expression of key genes related to glucose sensing and hormone secretion relative to subpopulations expressing only one or neither TF. Moreover, all subpopulations were identified in native pancreatic tissue from multiple donors. By Patch-Seq, MAFA/MAFB-coexpressing β cells showed enhanced electrophysiological activity. Thus, these results indicate that combinatorial TF expression in islet α and β cells predicts highly functional, mature subpopulations.
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http://dx.doi.org/10.1172/jci.insight.151621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492318PMC
September 2021

A developmental lineage-based gene co-expression network for mouse pancreatic β-cells reveals a role for in pancreas development.

Development 2021 03 21;148(6). Epub 2021 Mar 21.

Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37232, USA

To gain a deeper understanding of pancreatic β-cell development, we used iterative weighted gene correlation network analysis to calculate a gene co-expression network (GCN) from 11 temporally and genetically defined murine cell populations. The GCN, which contained 91 distinct modules, was then used to gain three new biological insights. First, we found that the clustered protocadherin genes are differentially expressed during pancreas development. Pcdhγ genes are preferentially expressed in pancreatic endoderm, Pcdhβ genes in nascent islets, and Pcdhα genes in mature β-cells. Second, after extracting sub-networks of transcriptional regulators for each developmental stage, we identified 81 zinc finger protein (ZFP) genes that are preferentially expressed during endocrine specification and β-cell maturation. Third, we used the GCN to select three ZFPs for further analysis by CRISPR mutagenesis of mice. null mice exhibited early postnatal lethality, and at E18.5 their pancreata exhibited a reduced number of pancreatic endocrine cells, alterations in exocrine cell morphology, and marked changes in expression of genes involved in protein translation, hormone secretion and developmental pathways in the pancreas. Together, our results suggest that developmentally oriented GCNs have utility for gaining new insights into gene regulation during organogenesis.
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http://dx.doi.org/10.1242/dev.196964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015253PMC
March 2021

Pancreatlas: Applying an Adaptable Framework to Map the Human Pancreas in Health and Disease.

Patterns (N Y) 2020 Nov 5;1(8):100120. Epub 2020 Oct 5.

Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Human tissue phenotyping generates complex spatial information from numerous imaging modalities, yet images typically become static figures for publication, and original data and metadata are rarely available. While comprehensive image maps exist for some organs, most resources have limited support for multiplexed imaging or have non-intuitive user interfaces. Therefore, we built a Pancreatlas resource that integrates several technologies into a unique interface, allowing users to access richly annotated web pages, drill down to individual images, and deeply explore data online. The current version of Pancreatlas contains over 800 unique images acquired by whole-slide scanning, confocal microscopy, and imaging mass cytometry, and is available at https://www.pancreatlas.org. To create this human pancreas-specific biological imaging resource, we developed a React-based web application and Python-based application programming interface, collectively called Flexible Framework for Integrating and Navigating Data (FFIND), which can be adapted beyond Pancreatlas to meet countless imaging or other structured data-management needs.
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http://dx.doi.org/10.1016/j.patter.2020.100120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691395PMC
November 2020

Quantitative Analysis of Adenosine-to-Inosine RNA Editing.

Methods Mol Biol 2021 ;2181:97-111

Training Program in Neuroscience, Vanderbilt University School of Medicine, Nashville, TN, USA.

The conversion of adenosine to inosine (A to I) by RNA editing represents a common posttranscriptional mechanism for diversification of both the transcriptome and proteome, and is a part of the cellular response for innate immune tolerance. Due to its preferential base-pairing with cytosine (C), inosine (I) is recognized as guanosine (G) by reverse transcriptase, as well as the cellular splicing and translation machinery. A-to-I editing events appear as A-G discrepancies between genomic DNA and cDNA sequences. Molecular analyses of RNA editing have leveraged these nucleoside differences to quantify RNA editing in ensemble populations of RNA transcripts and within individual cDNAs using high-throughput sequencing or Sanger sequencing-derived analysis of electropherogram peak heights. Here, we briefly review and compare these methods of RNA editing quantification, as well as provide experimental protocols by which such analyses may be achieved.
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http://dx.doi.org/10.1007/978-1-0716-0787-9_7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208106PMC
March 2021

Excitotoxicity and Overnutrition Additively Impair Metabolic Function and Identity of Pancreatic β-Cells.

Diabetes 2020 07 24;69(7):1476-1491. Epub 2020 Apr 24.

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN

A sustained increase in intracellular Ca concentration (referred to hereafter as excitotoxicity), brought on by chronic metabolic stress, may contribute to pancreatic β-cell failure. To determine the additive effects of excitotoxicity and overnutrition on β-cell function and gene expression, we analyzed the impact of a high-fat diet (HFD) on knockout mice. Excitotoxicity caused β-cells to be more susceptible to HFD-induced impairment of glucose homeostasis, and these effects were mitigated by verapamil, a Ca channel blocker. Excitotoxicity, overnutrition, and the combination of both stresses caused similar but distinct alterations in the β-cell transcriptome, including additive increases in genes associated with mitochondrial energy metabolism, fatty acid β-oxidation, and mitochondrial biogenesis and their key regulator Overnutrition worsened excitotoxicity-induced mitochondrial dysfunction, increasing metabolic inflexibility and mitochondrial damage. In addition, excitotoxicity and overnutrition, individually and together, impaired both β-cell function and identity by reducing expression of genes important for insulin secretion, cell polarity, cell junction, cilia, cytoskeleton, vesicular trafficking, and regulation of β-cell epigenetic and transcriptional program. Sex had an impact on all β-cell responses, with male animals exhibiting greater metabolic stress-induced impairments than females. Together, these findings indicate that a sustained increase in intracellular Ca, by altering mitochondrial function and impairing β-cell identity, augments overnutrition-induced β-cell failure.
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http://dx.doi.org/10.2337/db19-1145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809715PMC
July 2020

Transgene-associated human growth hormone expression in pancreatic β-cells impairs identification of sex-based gene expression differences.

Am J Physiol Endocrinol Metab 2019 02 11;316(2):E196-E209. Epub 2018 Dec 11.

Department of Cell and Developmental Biology, Vanderbilt University , Nashville, Tennessee.

Fluorescent protein reporter genes are widely used to identify and sort murine pancreatic β-cells. In this study, we compared use of the MIP-GFP transgene, which exhibits aberrant expression of human growth hormone (hGH), with a newly derived Ins2 allele that lacks hGH expression on the expression of sex-specific genes. β-Cells from MIP-GFP transgenic mice exhibit changes in the expression of 7,733 genes, or greater than half of their transcriptome, compared with β-cells from Ins2 mice. To determine how these differences might affect a typical differential gene expression study, we analyzed the effect of sex on gene expression using both reporter lines. Six hundred fifty-seven differentially expressed genes were identified between male and female β-cells containing the Ins2 allele. Female β-cells exhibit higher expression of Xist, Tmed9, Arpc3, Eml2, and several islet-enriched transcription factors, including Nkx2-2 and Hnf4a, whereas male β-cells exhibited a generally higher expression of genes involved in cell cycle regulation. In marked contrast, the same male vs. female comparison of β-cells containing the MIP-GFP transgene revealed only 115 differentially expressed genes, and comparison of the 2 lists of differentially expressed genes revealed only 17 that were common to both analyses. These results indicate that 1) male and female β-cells differ in their expression of key transcription factors and cell cycle regulators and 2) the MIP-GFP transgene may attenuate sex-specific differences that distinguish male and female β-cells, thereby impairing the identification of sex-specific variations.
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http://dx.doi.org/10.1152/ajpendo.00229.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397359PMC
February 2019

Chronic β-Cell Depolarization Impairs β-Cell Identity by Disrupting a Network of Ca-Regulated Genes.

Diabetes 2017 08 26;66(8):2175-2187. Epub 2017 May 26.

Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN

We used mice lacking , a key component of the β-cell K-channel, to analyze the effects of a sustained elevation in the intracellular Ca concentration ([Ca]) on β-cell identity and gene expression. Lineage tracing analysis revealed the conversion of β-cells lacking into pancreatic polypeptide cells but not to α- or δ-cells. RNA-sequencing analysis of FACS-purified β-cells confirmed an increase in gene expression and revealed altered expression of more than 4,200 genes, many of which are involved in Ca signaling, the maintenance of β-cell identity, and cell adhesion. The expression of and , two highly upregulated genes, is closely correlated with membrane depolarization, suggesting their use as markers for an increase in [Ca] Moreover, a bioinformatics analysis predicts that many of the dysregulated genes are regulated by common transcription factors, one of which, , was confirmed to be directly controlled by Ca influx in β-cells. Interestingly, among the upregulated genes is , a putative marker of β-cell dedifferentiation, and other genes associated with β-cell failure. Taken together, our results suggest that chronically elevated β-cell [Ca] in islets contributes to the alteration of β-cell identity, islet cell numbers and morphology, and gene expression by disrupting a network of Ca-regulated genes.
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http://dx.doi.org/10.2337/db16-1355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521870PMC
August 2017

Research resource: dkCOIN, the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) consortium interconnectivity network: a pilot program to aggregate research resources generated by multiple research consortia.

Mol Endocrinol 2012 Oct 25;26(10):1675-81. Epub 2012 Jun 25.

Ph.D, Vanderbilt Center Stem for Cell Biology, Vanderbilt University Medical Center, 1207 17th Avenue South, Suite 200, Nashville, Tennessee 37203, USA.

The National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) supports multiple basic science consortia that generate high-content datasets, reagent resources, and methodologies, in the fields of kidney, urology, hematology, digestive, and endocrine diseases, as well as metabolic diseases such as diabetes and obesity. These currently include the Beta Cell Biology Consortium, the Nuclear Receptor Signaling Atlas, the Diabetic Complications Consortium, and the Mouse Metabolic Phenotyping Centers. Recognizing the synergy that would accrue from aggregating information generated and curated by these initiatives in a contiguous informatics network, we created the NIDDK Consortium Interconnectivity Network (dkCOIN; www.dkcoin.org). The goal of this pilot project, organized by the NIDDK, was to establish a single point of access to a toolkit of interconnected resources (datasets, reagents, and protocols) generated from individual consortia that could be readily accessed by biologists of diverse backgrounds and research interests. During the pilot phase of this activity dkCOIN collected nearly 2000 consortium-curated resources, including datasets (functional genomics) and reagents (mouse strains, antibodies, and adenoviral constructs) and built nearly 3000 resource-to-resource connections, thereby demonstrating the feasibility of further extending this database in the future. Thus, dkCOIN promises to be a useful informatics solution for rapidly identifying useful resources generated by participating research consortia.
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http://dx.doi.org/10.1210/me.2012-1077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3458218PMC
October 2012

A role for collagen IV cross-links in conferring immune privilege to the Goodpasture autoantigen: structural basis for the crypticity of B cell epitopes.

J Biol Chem 2008 Aug 22;283(33):22737-48. Epub 2008 May 22.

Center for Matrix Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.

The detailed structural basis for the cryptic nature (crypticity) of a B cell epitope harbored by an autoantigen is unknown. Because the immune system may be ignorant of the existence of such "cryptic" epitopes, their exposure could be an important feature in autoimmunity. Here we investigated the structural basis for the crypticity of the epitopes of the Goodpasture autoantigen, the alpha3alpha4alpha5 noncollagenous-1 (NC1) hexamer, a globular domain that connects two triple-helical molecules of the alpha3alpha4alpha5 collagen IV network. The NC1 hexamer occurs in two isoforms as follows: the M-isoform composed of monomer subunits in which the epitopes are accessible to autoantibodies, and the D-isoform composed of both monomer and dimer subunits in which the epitopes are cryptic. The D-isoform was characterized with respect to quaternary structure, as revealed by mass spectrometry of dimer subunits, homology modeling, and molecular dynamics simulation. The results revealed that the D-isoform contains two kinds of cross-links as follows: S-hydroxylysyl-methionine and S-lysyl-methionine cross-links, which stabilize the alpha3alpha5-heterodimers and alpha4alpha4-homodimers, respectively. Construction and analysis of a three-dimensional model of the D-isoform of the alpha3alpha4alpha5 NC1 hexamer revealed that crypticity is a consequence of the following: (a) sequestration of key residues between neighboring subunits that are stabilized by domain-swapping interactions, and (b) by cross-linking of subunits at the trimer-trimer interface, which stabilizes the structural integrity of the NC1 hexamer and protects against binding of autoantibodies. The sequestrated epitopes and cross-linked subunits represent a novel structural mechanism for conferring immune privilege at the level of quaternary structure. Perturbation of the quaternary structure may be a key factor in the etiology of Goodpasture disease.
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http://dx.doi.org/10.1074/jbc.M803451200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2504875PMC
August 2008

Molecular recognition in the assembly of collagens: terminal noncollagenous domains are key recognition modules in the formation of triple helical protomers.

J Biol Chem 2006 Dec 2;281(50):38117-21. Epub 2006 Nov 2.

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-2372, USA.

The alpha-chains of the collagen superfamily are encoded with information that specifies self-assembly into fibrils, microfibrils, and networks that have diverse functions in the extracellular matrix. A key self-organizing step, common to all collagen types, is trimerization that selects, binds, and registers cognate alpha-chains for assembly of triple helical protomers that subsequently oligomerize into specific suprastructures. In this article, we review recent findings on the mechanism of chain selection and infer that terminal noncollagenous domains function as recognition modules in trimerization and are therefore key determinants of specificity in the assembly of suprastructures. This mechanism is also illustrated with computer-generated animations.
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http://dx.doi.org/10.1074/jbc.R600025200DOI Listing
December 2006

Mechanism of chain selection in the assembly of collagen IV: a prominent role for the alpha2 chain.

J Biol Chem 2006 Mar 22;281(9):6058-69. Epub 2005 Dec 22.

Department of Medicine, Vanderbilt University School of Medicine, Medical Center, 1161 21st Avenue South, Nashville, TN 37232, USA.

Collagens comprise a large superfamily of extracellular matrix proteins that play diverse roles in tissue function. The mechanism by which newly synthesized collagen chains recognize each other and assemble into specific triple-helical molecules is a fundamental question that remains unanswered. Emerging evidence suggests a role for the non-collagenous domain (NC1) located at the C-terminal end of each chain. In this study, we have investigated the molecular mechanism underlying chain selection in the assembly of collagen IV. Using surface plasmon resonance, we have determined the kinetics of interaction and assembly of the alpha1(IV) and alpha2(IV) NC1 domains. We show that the differential affinity of alpha2(IV) NC1 domain for dimer formation underlies the driving force in the mechanism of chain discrimination. Given its characteristic domain recognition and affinity for the alpha1(IV) NC1 domain, we conclude that the alpha2(IV) chain plays a regulatory role in directing chain composition in the assembly of (alpha1)(2)alpha2 triple-helical molecule. Detailed crystal structure analysis of the [(alpha1)(2)alpha2](2) NC1 hexamer and sequence alignments of the NC1 domains of all six alpha-chains from mammalian species revealed the residues involved in the molecular recognition of NC1 domains. We further identified a hypervariable region of 15 residues and a beta-hairpin structural motif of 13 residues as two prominent regions that mediate chain selection in the assembly of collagen IV. To our knowledge, this report is the first to combine kinetics and structural data to describe molecular basis for chain selection in the assembly of a collagen molecule.
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http://dx.doi.org/10.1074/jbc.M506555200DOI Listing
March 2006

Structural and functional characterization of pi bulges and other short intrahelical deformations.

Structure 2004 Jan;12(1):133-44

Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA.

We data-mined the Protein Data Bank for short intrahelical deformations, including pi bulges. These are defined as a contiguous stretch of intrahelical residues deviating from the standard alpha-helical i-->i-4 hydrogen bonding pattern, bilaterally flanked by at least one alpha-helical turn resulting in a helix kink of less than 40 degrees. We find that such motifs exist in 4.7% of a PDB subset filtered by quality metrics (resolution <2.5 A, R-factor <0.25, sequence identity <35%). These are typically characterized by at least one i-->i-5 main chain hydrogen bond, with energetically favorable main chain dihedral angles, followed by a variable number of main chain carbonyl groups that do not accept intrahelical main chain hydrogen bonds. Their stabilization commonly occurs via hydrogen bonding to water molecules or polar groups. Numerous deformations are implicated in basic yet vital functional roles, commonly as ligand binding site contributors.
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http://dx.doi.org/10.1016/j.str.2003.12.001DOI Listing
January 2004

Global structural changes in annexin 12. The roles of phospholipid, Ca2+, and pH.

J Biol Chem 2003 Aug 19;278(32):30227-34. Epub 2003 May 19.

Department of Biochemistry and Molecular Biology, Keck School of Medicine, Zilkha Neurogenetic Institute and Arnold and Mabel Beckman Macular Research Center, University of Southern California, Los Angeles, California 90033, USA.

Ca2+-dependent membrane interaction has long been recognized as a general property of the annexin (ANX) family of proteins. More recently, it has become clear that ANXs can also undergo Ca2+-independent membrane interactions at mildly acidic pH. Here we use site-directed spin labeling in combination with circular dichroism and biochemical labeling methods to compare the structure and membrane topography of these two different membrane-bound forms of ANX12. Our results reveal strong similarities between the solution structure and the structure of the Ca2+-dependent membrane-bound form at neutral pH. In contrast, all Ca2+-independent membrane interactions tested resulted in large scale conformational changes and membrane insertion. Pairs of spin labels that were in close proximity across the interface of different domains of the protein in both the soluble and Ca2+-dependent membrane form were >25 A apart in the Ca2+-independent membrane-bound form. Despite these major conformational changes, the overall secondary structure content did not appear to be strongly altered and ANX12 remained largely helical. Thus, Ca2+-independent membrane interaction leads to massive refolding but not unfolding. Refolding did not occur at low pH in the absence of membranes but occurred within a few seconds after phospholipid vesicles were added. The phospholipid composition of the vesicles was an important modulator of Ca2+-independent membrane interaction. For example, cardiolipin-containing vesicles induced Ca2+-independent membrane interaction even at near neutral pH, thereby raising the possibility that lipid composition could induce relatively rapid Ca2+-independent membrane interaction in vivo.
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http://dx.doi.org/10.1074/jbc.M301228200DOI Listing
August 2003

X-ray crystallographic analysis of lipid-protein interactions in the bacteriorhodopsin purple membrane.

Annu Rev Biophys Biomol Struct 2003 10;32:285-310. Epub 2003 Feb 10.

Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, California 92697-3900, USA.

The past decade has witnessed increasingly detailed insights into the structural mechanism of the bacteriorhodopsin photocycle. Concurrently, there has been much progress within our knowledge pertaining to the lipids of the purple membrane, including the discovery of new lipids and the overall effort to localize and identify each lipid within the purple membrane. Therefore, there is a need to classify this information to generalize the findings. We discuss the properties and roles of haloarchaeal lipids and present the structural data as individual case studies. Lipid-protein interactions are discussed in the context of structure-function relationships. A brief discussion of the possibility that bacteriorhodopsin functions as a light-driven inward hydroxide pump rather than an outward proton pump is also presented.
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http://dx.doi.org/10.1146/annurev.biophys.32.110601.142516DOI Listing
November 2003
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