762 results match your criteria c-terminus combined

Targeting CDK9 for Anti-Cancer Therapeutics.

Cancers (Basel) 2021 May 1;13(9). Epub 2021 May 1.

Department of Gynecology and Obstetrics, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.

Cyclin Dependent Kinase 9 (CDK9) is one of the most important transcription regulatory members of the CDK family. In conjunction with its main cyclin partner-Cyclin T1, it forms the Positive Transcription Elongation Factor b (P-TEFb) whose primary function in eukaryotic cells is to mediate the positive transcription elongation of nascent mRNA strands, by phosphorylating the S2 residues of the YSPTSPS tandem repeats at the C-terminus domain (CTD) of RNA Polymerase II (RNAP II). To aid in this process, P-TEFb also simultaneously phosphorylates and inactivates a number of negative transcription regulators like 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) Sensitivity-Inducing Factor (DSIF) and Negative Elongation Factor (NELF). Read More

View Article and Full-Text PDF

Targeted modification of the Per2 clock gene alters circadian function in mPer2luciferase (mPer2Luc) mice.

PLoS Comput Biol 2021 May 28;17(5):e1008987. Epub 2021 May 28.

Laboratory of Biological Rhythms, Institute of Physiology, the Czech Academy of Sciences, Prague, Czech Republic.

Modification of the Per2 clock gene in mPer2Luc reporter mice significantly alters circadian function. Behavioral period in constant dark is lengthened, and dissociates into two distinct components in constant light. Rhythms exhibit increased bimodality, enhanced phase resetting to light pulses, and altered entrainment to scheduled feeding. Read More

View Article and Full-Text PDF

Design of a new multi-epitope vaccine against based on T and B cell epitopes using bioinformatics methods.

Epidemiol Infect 2021 May 25;149:e136. Epub 2021 May 25.

Department of Immunology, College of Basic Medicine, Xinjiang Medical University, Urumqi, 830011Xinjiang, China.

Brucellosis is one of the most serious and widespread zoonotic diseases, which seriously threatens human health and the national economy. This study was based on the T/B dominant epitopes of Brucella outer membrane protein 22 (Omp22), outer membrane protein 19 (Omp19) and outer membrane protein 28 (Omp28), with bioinformatics methods to design a safe and effective multi-epitope vaccine. The amino acid sequences of the proteins were found in the National Center for Biotechnology Information (NCBI) database, and the signal peptides were predicted by the SignaIP-5. Read More

View Article and Full-Text PDF

Sec17/Sec18 can support membrane fusion without help from completion of SNARE zippering.

Elife 2021 May 4;10. Epub 2021 May 4.

Department of Biochemistry and Cell Biology Geisel School of Medicine at Dartmouth, Hanover, United States.

Membrane fusion requires R-, Qa-, Qb-, and Qc-family SNAREs that zipper into RQaQbQc coiled coils, driven by the sequestration of apolar amino acids. Zippering has been thought to provide all the force driving fusion. Sec17/αSNAP can form an oligomeric assembly with SNAREs with the Sec17 C-terminus bound to Sec18/NSF, the central region bound to SNAREs, and a crucial apolar loop near the N-terminus poised to insert into membranes. Read More

View Article and Full-Text PDF

Stability of Engineered Ferritin Nanovaccines Investigated by Combined Molecular Simulation and Experiments.

J Phys Chem B 2021 04 7;125(15):3830-3842. Epub 2021 Apr 7.

School of Chemical Engineering and Advanced Materials, The University of Adelaide, Adelaide, South Australia 5005, Australia.

Human ferritin is regarded as an attractive and promising vaccine platform because of its uniform structure, good plasticity, and desirable thermal and chemical stabilities. Besides, it is biocompatible and presumed safe when used as a vaccine carrier. However, there is a lack of knowledge of how different antigen insertion sites on the ferritin nanocage impact the resulting protein stability and performance. Read More

View Article and Full-Text PDF

The Accessory Helix of Complexin Stabilizes a Partially Unzippered State of the SNARE Complex and Mediates the Complexin Clamping Function .

eNeuro 2021 Mar-Apr;8(2). Epub 2021 Apr 7.

Ophthalmology, Visual and Anatomical Sciences Department, Wayne State University School of Medicine, Detroit, MI 48202

Spontaneous synaptic transmission is regulated by the protein complexin (Cpx). Cpx binds the SNARE complex, a coil-coiled four-helical bundle that mediates the attachment of a synaptic vesicle (SV) to the presynaptic membrane (PM). Cpx is thought to clamp spontaneous fusion events by stabilizing a partially unraveled state of the SNARE bundle; however, the molecular detail of this mechanism is still debated. Read More

View Article and Full-Text PDF

Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors.

Elife 2021 Mar 4;10. Epub 2021 Mar 4.

Department of Biochemistry and Microbiology, University of Victoria, Victoria, Canada.

Class I Phosphoinositide 3-kinases (PI3Ks) are master regulators of cellular functions, with the class IB PI3K catalytic subunit (p110γ) playing key roles in immune signalling. p110γ is a key factor in inflammatory diseases and has been identified as a therapeutic target for cancers due to its immunomodulatory role. Using a combined biochemical/biophysical approach, we have revealed insight into regulation of kinase activity, specifically defining how immunodeficiency and oncogenic mutations of R1021 in the C-terminus can inactivate or activate enzyme activity. Read More

View Article and Full-Text PDF

Identification of additional outer segment targeting signals in zebrafish rod opsin.

J Cell Sci 2021 Mar 26;134(6). Epub 2021 Mar 26.

Bateson Centre and Department of Biomedical Science, University of Sheffield, Firth Court, Western Bank, Sheffield, S10 2TN, UK.

In vertebrate photoreceptors, opsins are highly concentrated in a morphologically distinct ciliary compartment known as the outer segment (OS). Opsin is synthesized in the cell body and transported to the OS at a remarkable rate of 100 to 1000 molecules per second. Opsin transport defects contribute to photoreceptor loss and blindness in human ciliopathies. Read More

View Article and Full-Text PDF

Cellular reprogramming with multigene activation by the delivery of CRISPR/dCas9 ribonucleoproteins via magnetic peptide-imprinted chitosan nanoparticles.

Mater Today Bio 2021 Jan 20;9:100091. Epub 2021 Jan 20.

Department of Chemical and Materials Engineering, National University of Kaohsiung, Kaohsiung, 81148, Taiwan.

Induced pluripotent stem cells are usually derived by reprogramming transcription factors (OSKM), such as octamer-binding transcription factor 4 (OCT4), (sex determining region Y)-box 2 (SOX2), Krüppel-like factor 4 (KLF4), and cellular proto-oncogene (c-Myc). However, the genomic integration of transcription factors risks the insertion of mutations into the genome of the target cells. Recently, the clustered regularly interspaced short palindromic repeat-associated protein 9 (CRISPR/Cas9) system has been used to edit genomes. Read More

View Article and Full-Text PDF
January 2021

Potent Bispecific Neutralizing Antibody Targeting Glycoprotein B and the gH/gL/pUL128/130/131 Complex of Human Cytomegalovirus.

Antimicrob Agents Chemother 2021 02 17;65(3). Epub 2021 Feb 17.

Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that can cause developmental disorders following congenital infection and life-threatening complications among transplant patients. Potent neutralizing monoclonal antibodies (MAbs) are promising drug candidates against HCMV infection. HCMV can infect a broad range of cell types. Read More

View Article and Full-Text PDF
February 2021

Addition of L-cysteine to the N- or C-terminus of the all-D-enantiomer [(KLAKLAK)] increases antimicrobial activities against multidrug-resistant and .

PeerJ 2020 30;8:e10176. Epub 2020 Nov 30.

Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo, Japan.

Background: Antimicrobial peptides have a broad spectrum of antimicrobial activities and are attracting attention as promising next-generation antibiotics against multidrug-resistant (MDR) bacteria. The all-d-enantiomer [(KLAKLAK)] has been reported to have antimicrobial activity against and , and to be resistant to protein degradation in bacteria because it is composed of D-enantiomer compounds. In this study, we demonstrated that modification of [(KLAKLAK)] by the addition of an L-cysteine residue to its N- or C- terminus markedly enhanced its antimicrobial activities against Gram-negative bacteria such as MDR , , and . Read More

View Article and Full-Text PDF
November 2020

Selection of GmSWEET39 for oil and protein improvement in soybean.

PLoS Genet 2020 11 11;16(11):e1009114. Epub 2020 Nov 11.

Donald Danforth Plant Science Center, St. Louis, MO, United States of America.

Soybean [Glycine max (L.) Merr.] was domesticated from wild soybean (G. Read More

View Article and Full-Text PDF
November 2020

A Transgenic Line That Reports CSF1R Protein Expression Provides a Definitive Marker for the Mouse Mononuclear Phagocyte System.

J Immunol 2020 12 2;205(11):3154-3166. Epub 2020 Nov 2.

Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Queensland 4102, Australia;

The proliferation, differentiation, and survival of cells of the mononuclear phagocyte system (MPS; progenitors, monocytes, macrophages, and classical dendritic cells) are controlled by signals from the M-CSF receptor (CSF1R). Cells of the MPS lineage have been identified using numerous surface markers and transgenic reporters, but none is both universal and lineage restricted. In this article, we report the development and characterization of a CSF1R reporter mouse. Read More

View Article and Full-Text PDF
December 2020

Cloning and Functional Characterization of Dihydroflavonol 4-Reductase Gene Involved in Anthocyanin Biosynthesis of Chrysanthemum.

Int J Mol Sci 2020 Oct 27;21(21). Epub 2020 Oct 27.

National Institute of Agricultural Sciences, Rural Development Administration, Jeonju 54874, Korea.

Dihydroflavonol 4-reductase (DFR) catalyzes a committed step in anthocyanin and proanthocyanidin biosynthesis by reducing dihydroflavonols to leucoanthocyanidins. However, the role of this enzyme in determining flower color in the economically important crop chrysanthemum ( Ramat.) is unknown. Read More

View Article and Full-Text PDF
October 2020

Intracellular activation of full-length human TREK-1 channel by hypoxia, high lactate, and low pH denotes polymodal integration by ischemic factors.

Pflugers Arch 2021 02 6;473(2):167-183. Epub 2020 Oct 6.

Molecular Biophysics Unit, Indian Institute of Science, Bangalore, Karnataka, 560012, India.

TREK-1, a two-pore domain potassium channel, responds to ischemic levels of intracellular lactate and acidic pH to provide neuroprotection. There are two splice variants of hTREK1: the shorter splice variant having a shorter N-terminus compared with the full-length hTREK1 with similar C-terminus sequence that is widely expressed in the brain. The shorter variant was reported to be irresponsive to hypoxia-a condition attributed to ischemia, which has put the neuroprotective role of hTREK-1 channel into question. Read More

View Article and Full-Text PDF
February 2021

Arming HSV-Based Oncolytic Viruses with the Ability to Redirect the Host's Innate Antiviral Immunity to Attack Tumor Cells.

Mol Ther Oncolytics 2020 Dec 6;19:33-46. Epub 2020 Sep 6.

Department of Biology and Biochemistry and Center for Nuclear Receptor and Cell Signaling, University of Houston, Houston, TX, USA.

One of the major hurdles for cancer immunotherapy is the host's innate antiviral defense mechanisms. They include innate immune cells, such as natural killer (NK) cells and macrophages, which can be recruited within hours to the site of injection to clear the introduced oncolytic viruses. Here, we report a strategy to redirect these infiltrating innate immune cells to attack tumor cells instead by arming herpes simplex virus (HSV)-derived oncolytic viruses with secreted chimeric molecules that can engage these innate immune cells with tumor cells to kill the latter. Read More

View Article and Full-Text PDF
December 2020

Mutational Analysis of Residues in PriA and PriC Affecting Their Ability To Interact with SSB in Escherichia coli K-12.

J Bacteriol 2020 11 4;202(23). Epub 2020 Nov 4.

Molecular and Cellular Biology Program, University of Massachusetts Amherst, Amherst, Massachusetts, USA

PriA and PriC recognize abandoned replication forks and direct reloading of the DnaB replicative helicase onto the lagging-strand template coated with single-stranded DNA-binding protein (SSB). Both PriA and PriC have been shown by biochemical and structural studies to physically interact with the C terminus of SSB. , these interactions trigger remodeling of the SSB on ssDNA. Read More

View Article and Full-Text PDF
November 2020

A Nonsense N -Terminus NFKB2 Mutation Leading to Haploinsufficiency in a Patient with a Predominantly Antibody Deficiency.

J Clin Immunol 2020 11 19;40(8):1093-1101. Epub 2020 Aug 19.

Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Building 10, Room 2C306, 10 Center Drive, MSC1508, Bethesda, MD, USA.

The noncanonical NF-κB pathway is implicated in diverse biological and immunological processes. Monoallelic C-terminus loss-of-function and gain-of-function mutations of NFKB2 have been recently identified as a cause of immunodeficiency manifesting with common variable immunodeficiency (CVID) or combined immunodeficiency (CID) phenotypes. Herein we report a family carrying a heterozygous nonsense mutation in NFKB2 (c. Read More

View Article and Full-Text PDF
November 2020

Structure and dynamics of the active Gs-coupled human secretin receptor.

Nat Commun 2020 08 18;11(1):4137. Epub 2020 Aug 18.

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ, 85259, USA.

The class B secretin GPCR (SecR) has broad physiological effects, with target potential for treatment of metabolic and cardiovascular disease. Molecular understanding of SecR binding and activation is important for its therapeutic exploitation. We combined cryo-electron microscopy, molecular dynamics, and biochemical cross-linking to determine a 2. Read More

View Article and Full-Text PDF

The C-terminal region of the oxidoreductase MIA40 stabilizes its cytosolic precursor during mitochondrial import.

BMC Biol 2020 08 6;18(1):96. Epub 2020 Aug 6.

Institute for Biochemistry, Redox Biochemistry, University of Cologne, Zuelpicher Str. 47a, 50674, Cologne, Germany.

Background: The mitochondrial intermembrane space (IMS) is home to proteins fulfilling numerous essential cellular processes, particularly in metabolism and mitochondrial function. All IMS proteins are nuclear encoded and synthesized in the cytosol and must therefore be correctly targeted and transported to the IMS, either through mitochondrial targeting sequences or conserved cysteines and the mitochondrial disulfide relay system. The mitochondrial oxidoreductase MIA40, which catalyzes disulfide formation in the IMS, is imported by the combined action of the protein AIFM1 and MIA40 itself. Read More

View Article and Full-Text PDF

Antinociceptive and Cytotoxic Activity of Opioid Peptides with Hydrazone and Hydrazide Moieties at the C-Terminus.

Molecules 2020 Jul 28;25(15). Epub 2020 Jul 28.

Department of Neuropeptides, Mossakowski Medical Research Centre Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland.

In the present contribution, we analyze the influence that C-terminal extension of short opioid peptide sequences by organic fragments has on receptor affinity, in vivo analgesic activity, and antimelanoma properties. The considered fragments were based on either acylhydrazone (NAH) or -acylhydrazide motifs combined with the 3,5-bis(trifluoromethyl)phenyl moiety. Eleven novel compounds were synthesized and subject to biological evaluation. Read More

View Article and Full-Text PDF

Efficient Therapeutic Delivery by a Novel Cell-Penetrating Peptide Derived from Acinus.

Cancers (Basel) 2020 Jul 10;12(7). Epub 2020 Jul 10.

INSERM UMRS976, Institut de Recherche Saint Louis, Hôpital Saint Louis, Bâtiment Hayem, 1 avenue Claude Vellefaux, 75010 Paris, France.

In this study, we have identified a novel cell-penetrating sequence, termed hAP10, from the C-terminus of the human protein Acinus. hAP10 was able to efficiently enter various normal and cancerous cells, likely through an endocytosis pathway, and to deliver an EGFP cargo to the cell interior. Cell penetration of a peptide, hAP10DR, derived from hAP10 by mutation of an aspartic acid residue to an arginine was dramatically increased. Read More

View Article and Full-Text PDF

Vancomycin C-Terminus Guanidine Modifications and Further Insights into an Added Mechanism of Action Imparted by a Peripheral Structural Modification.

ACS Infect Dis 2020 08 14;6(8):2169-2180. Epub 2020 Jul 14.

Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States.

A series of vancomycin C-terminus guanidine modifications is disclosed that improves antimicrobial activity, enhances the durability of antimicrobial action against selection or induction of resistance, and introduces a synergistic mechanism of action independent of d-Ala-d-Ala binding and inhibition of cell wall biosynthesis. The added mechanism of action results in induced bacterial cell permeability, which we show may involve interaction with cell envelope teichoic acid. Significantly, the compounds examined that contain two combined peripheral modifications, a (4-chlorobiphenyl)methyl (CBP) and C-terminus guanidinium modification, offer opportunities for new treatments against not only vancomycin-sensitive but especially vancomycin-resistant bacteria where they act by two synergistic and now durable mechanisms of action independent of d-Ala-d-Ala/d-Lac binding and display superb antimicrobial potencies (MIC 0. Read More

View Article and Full-Text PDF

Fragmentation of Human Neutrophil α-Defensin 4 to Combat Multidrug Resistant Bacteria.

Front Microbiol 2020 3;11:1147. Epub 2020 Jun 3.

Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, Human Genomics and Metagenomics in Metabolism, University of Copenhagen, Copenhagen, Denmark.

The occurrence and spread of multidrug-resistant bacteria is a prominent health concern. To curb this urgent threat, new innovative strategies pursuing novel antimicrobial agents are of the utmost importance. Here, we unleashed the antimicrobial activity of human neutrophil peptide-4 (HNP-4) by tryptic digestion. Read More

View Article and Full-Text PDF

Investigation of binding modes of spider toxin-human voltage-gated sodium channel subtybe 1.7.

J Biomol Struct Dyn 2020 Jun 22:1-9. Epub 2020 Jun 22.

College of plant protection, Henan Agricultural University, Zhengzhou, P.R China.

ABSTRACTSThe human voltage-gated sodium channel subtype 1.7 (hNaV1.7) is an attractive target for the development of potent and selective novel analgesics. Read More

View Article and Full-Text PDF

XPC as breast cancer susceptibility gene: evidence from genetic profiling, statistical inferences and protein structural analysis.

Breast Cancer 2020 Nov 19;27(6):1168-1176. Epub 2020 Jun 19.

Breast Clinic, Combined Military Hospital, Rawalpindi, Pakistan.

Background: Gene polymorphisms that affect nucleotide excision repair (NER) pathway may link with higher susceptibility of breast cancer (BC); however, the significance of these associations may vary conferring to the individual ethnicity. Xeroderma pigmentosum complementation gene (XPC) plays a substantial role in recognizing damaged DNA during NER process.

Objective And Methods: To estimate the relationship among XPC polymorphisms and breast cancer (BC) risk, we carried out a case-control-association study with 493 BC cases and 387 controls using TETRA-ARMS-PCR. Read More

View Article and Full-Text PDF
November 2020

The Arabidopsis N -acetyltransferase NAA60 locates to the plasma membrane and is vital for the high salt stress response.

New Phytol 2020 10 16;228(2):554-569. Epub 2020 Jul 16.

Centre for Organismal Studies Heidelberg, Heidelberg University, Heidelberg, 69120, Germany.

In humans and plants, N-terminal acetylation plays a central role in protein homeostasis, affects 80% of proteins in the cytoplasm and is catalyzed by five ribosome-associated N-acetyltransferases (NatA-E). Humans also possess a Golgi-associated NatF (HsNAA60) that is essential for Golgi integrity. Remarkably, NAA60 is absent in fungi and has not been identified in plants. Read More

View Article and Full-Text PDF
October 2020

Daxx Inhibits HIV-1 Reverse Transcription and Uncoating in a SUMO-Dependent Manner.

Viruses 2020 06 11;12(6). Epub 2020 Jun 11.

Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, CNRS, 34090 Montpellier, France.

Death domain-associated protein 6 (Daxx) is a multifunctional, ubiquitously expressed and highly conserved chaperone protein involved in numerous cellular processes, including apoptosis, transcriptional repression, and carcinogenesis. In 2015, we identified Daxx as an antiretroviral factor that interfered with HIV-1 replication by inhibiting the reverse transcription step. In the present study, we sought to unravel the molecular mechanism of Daxx-mediated restriction and, in particular, to identify the protein(s) that Daxx targets in order to achieve its antiviral activity. Read More

View Article and Full-Text PDF

Both N-Terminal and C-Terminal Histidine Residues of the Prion Protein Are Essential for Copper Coordination and Neuroprotective Self-Regulation.

J Mol Biol 2020 07 28;432(16):4408-4425. Epub 2020 May 28.

Department of Chemistry and Biochemistry, University of California, 1156 High Street, Santa Cruz, CA 95064, USA. Electronic address:

The cellular prion protein (PrP) comprises two domains: a globular C-terminal domain and an unstructured N-terminal domain. Recently, copper has been observed to drive tertiary contact in PrP, inducing a neuroprotective cis interaction that structurally links the protein's two domains. The location of this interaction on the C terminus overlaps with the sites of human pathogenic mutations and toxic antibody docking. Read More

View Article and Full-Text PDF

Signalling, trafficking and glucoregulatory properties of glucagon-like peptide-1 receptor agonists exendin-4 and lixisenatide.

Br J Pharmacol 2020 09 19;177(17):3905-3923. Epub 2020 Jun 19.

Section of Endocrinology and Investigative Medicine, Imperial College London, London, UK.

Background And Purpose: Amino acid substitutions at the N-termini of glucagon-like peptide-1 (GLP-1) receptor agonist peptides result in distinct patterns of intracellular signalling, sub-cellular trafficking and efficacy in vivo. Here, we to determine whether sequence differences at the ligand C-termini of clinically approved GLP-1 receptor agonists exendin-4 and lixisenatide lead to similar phenomena.

Experimental Approach: Exendin-4, lixisenatide and N-terminally substituted analogues with biased signalling characteristics were compared across a range of in vitro trafficking and signalling assays in different cell types. Read More

View Article and Full-Text PDF
September 2020