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Functional and structural similarity of human DNA primase [4Fe4S] cluster domain constructs.
Holt ME, Salay LE, O'Brien E, Barton JK, Chazin WJ
(2018) PLoS One 13: e0209345
MeSH Terms: Binding Sites, Circular Dichroism, Crystallography, X-Ray, DNA, DNA Primase, Molecular Docking Simulation, Nuclear Magnetic Resonance, Biomolecular, Oxidation-Reduction, Protein Binding, Protein Domains, Protein Structure, Secondary, RNA
Show Abstract · Added March 26, 2019
The regulatory subunit of human DNA primase has a C-terminal domain (p58C) that contains a [4Fe4S] cluster and binds DNA. Previous electrochemical analysis of a p58C construct revealed that its affinity for DNA is sensitive to the redox state of the [4Fe4S] cluster. Concerns about the validity of this conclusion have been raised, based in part on differences in X-ray crystal structures of the p58C272-464 construct used for that study and that of a N-terminally shifted p58C266-456 construct and consequently, an assumption that p58C272-464 has abnormal physical and functional properties. To address this controversy, a new p58C266-464 construct containing all residues was crystallized under the conditions previously used for crystallizing p58C272-464, and the solution structures of both constructs were assessed using circular dichroism and NMR spectroscopy. In the new crystal structure, p58C266-464 exhibits the same elements of secondary structure near the DNA binding site as observed in the crystal structure of p58C272-464. Moreover, in solution, circular dichroism and 15N,1H-heteronuclear single quantum coherence (HSQC) NMR spectra show there are no significant differences in the distribution of secondary structures or in the tertiary structure or the two constructs. To validate that the two constructs have the same functional properties, binding of a primed DNA template was measured using a fluorescence-based DNA binding assay, and the affinities for this substrate were the same (3.4 ± 0.5 μM and 2.7 ± 0.3 μM, respectively). The electrochemical properties of p58C266-464 were also measured and this p58C construct was able to engage in redox switching on DNA with the same efficiency as p58C272-464. Together, these results show that although p58C can be stabilized in different conformations in the crystalline state, in solution there is effectively no difference in the structure and functional properties of p58C constructs of different lengths.
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12 MeSH Terms
Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels.
Tin A, Li Y, Brody JA, Nutile T, Chu AY, Huffman JE, Yang Q, Chen MH, Robinson-Cohen C, Macé A, Liu J, Demirkan A, Sorice R, Sedaghat S, Swen M, Yu B, Ghasemi S, Teumer A, Vollenweider P, Ciullo M, Li M, Uitterlinden AG, Kraaij R, Amin N, van Rooij J, Kutalik Z, Dehghan A, McKnight B, van Duijn CM, Morrison A, Psaty BM, Boerwinkle E, Fox CS, Woodward OM, Köttgen A
(2018) Nat Commun 9: 4228
MeSH Terms: Exome, Genetic Predisposition to Disease, Glucose Transport Proteins, Facilitative, Humans, Kidney Function Tests, Meta-Analysis as Topic, Organic Anion Transporters, Organic Cation Transport Proteins, Protein Structure, Secondary, Uric Acid
Show Abstract · Added January 3, 2019
Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10) and SLC2A9 (p = 4.5 × 10). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout.
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MeSH Terms
Bid maintains mitochondrial cristae structure and function and protects against cardiac disease in an integrative genomics study.
Salisbury-Ruf CT, Bertram CC, Vergeade A, Lark DS, Shi Q, Heberling ML, Fortune NL, Okoye GD, Jerome WG, Wells QS, Fessel J, Moslehi J, Chen H, Roberts LJ, Boutaud O, Gamazon ER, Zinkel SS
(2018) Elife 7:
MeSH Terms: Animals, Apoptosis, BH3 Interacting Domain Death Agonist Protein, Beclin-1, Cell Respiration, Fibrosis, Gene Expression Regulation, Genome-Wide Association Study, Genomics, Heart Diseases, Heart Ventricles, Humans, Mice, Inbred C57BL, Mitochondria, Mitochondrial Proton-Translocating ATPases, Mutation, Myeloid Progenitor Cells, Myocardial Infarction, Myocytes, Cardiac, Polymorphism, Single Nucleotide, Protein Multimerization, Protein Structure, Secondary, Protein Subunits, Reactive Oxygen Species, Reproducibility of Results, Up-Regulation
Show Abstract · Added December 11, 2018
Bcl-2 family proteins reorganize mitochondrial membranes during apoptosis, to form pores and rearrange cristae. In vitro and in vivo analysis integrated with human genetics reveals a novel homeostatic mitochondrial function for Bcl-2 family protein Bid. Loss of full-length Bid results in apoptosis-independent, irregular cristae with decreased respiration. mice display stress-induced myocardial dysfunction and damage. A gene-based approach applied to a biobank, validated in two independent GWAS studies, reveals that decreased genetically determined BID expression associates with myocardial infarction (MI) susceptibility. Patients in the bottom 5% of the expression distribution exhibit >4 fold increased MI risk. Carrier status with nonsynonymous variation in Bid's membrane binding domain, Bid, associates with MI predisposition. Furthermore, Bid but not Bid associates with Mcl-1, previously implicated in cristae stability; decreased MCL-1 expression associates with MI. Our results identify a role for Bid in homeostatic mitochondrial cristae reorganization, that we link to human cardiac disease.
© 2018, Salisbury-Ruf et al.
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26 MeSH Terms
Structural Mechanism of Functional Modulation by Gene Splicing in NMDA Receptors.
Regan MC, Grant T, McDaniel MJ, Karakas E, Zhang J, Traynelis SF, Grigorieff N, Furukawa H
(2018) Neuron 98: 521-529.e3
MeSH Terms: Animals, Cell Line, Female, HEK293 Cells, Humans, Insecta, Protein Splicing, Protein Structure, Secondary, Protein Structure, Tertiary, Receptors, N-Methyl-D-Aspartate, Xenopus laevis
Show Abstract · Added April 10, 2019
Alternative gene splicing gives rise to N-methyl-D-aspartate (NMDA) receptor ion channels with defined functional properties and unique contributions to calcium signaling in a given chemical environment in the mammalian brain. Splice variants possessing the exon-5-encoded motif at the amino-terminal domain (ATD) of the GluN1 subunit are known to display robustly altered deactivation rates and pH sensitivity, but the underlying mechanism for this functional modification is largely unknown. Here, we show through cryoelectron microscopy (cryo-EM) that the presence of the exon 5 motif in GluN1 alters the local architecture of heterotetrameric GluN1-GluN2 NMDA receptors and creates contacts with the ligand-binding domains (LBDs) of the GluN1 and GluN2 subunits, which are absent in NMDA receptors lacking the exon 5 motif. The unique interactions established by the exon 5 motif are essential to the stability of the ATD/LBD and LBD/LBD interfaces that are critically involved in controlling proton sensitivity and deactivation.
Copyright © 2018 Elsevier Inc. All rights reserved.
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11 MeSH Terms
Mechanisms of KCNQ1 channel dysfunction in long QT syndrome involving voltage sensor domain mutations.
Huang H, Kuenze G, Smith JA, Taylor KC, Duran AM, Hadziselimovic A, Meiler J, Vanoye CG, George AL, Sanders CR
(2018) Sci Adv 4: eaar2631
MeSH Terms: Cell Membrane, HEK293 Cells, Humans, KCNQ1 Potassium Channel, Leupeptins, Long QT Syndrome, Loss of Function Mutation, Magnetic Resonance Spectroscopy, Mutant Proteins, Mutation, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Protein Domains, Protein Folding, Protein Structure, Secondary, Proteolysis
Show Abstract · Added March 14, 2018
Mutations that induce loss of function (LOF) or dysfunction of the human KCNQ1 channel are responsible for susceptibility to a life-threatening heart rhythm disorder, the congenital long QT syndrome (LQTS). Hundreds of mutations have been identified, but the molecular mechanisms responsible for impaired function are poorly understood. We investigated the impact of 51 KCNQ1 variants with mutations located within the voltage sensor domain (VSD), with an emphasis on elucidating effects on cell surface expression, protein folding, and structure. For each variant, the efficiency of trafficking to the plasma membrane, the impact of proteasome inhibition, and protein stability were assayed. The results of these experiments combined with channel functional data provided the basis for classifying each mutation into one of six mechanistic categories, highlighting heterogeneity in the mechanisms resulting in channel dysfunction or LOF. More than half of the KCNQ1 LOF mutations examined were seen to destabilize the structure of the VSD, generally accompanied by mistrafficking and degradation by the proteasome, an observation that underscores the growing appreciation that mutation-induced destabilization of membrane proteins may be a common human disease mechanism. Finally, we observed that five of the folding-defective LQTS mutant sites are located in the VSD S0 helix, where they interact with a number of other LOF mutation sites in other segments of the VSD. These observations reveal a critical role for the S0 helix as a central scaffold to help organize and stabilize the KCNQ1 VSD and, most likely, the corresponding domain of many other ion channels.
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16 MeSH Terms
The molecular basis of subtype selectivity of human kinin G-protein-coupled receptors.
Joedicke L, Mao J, Kuenze G, Reinhart C, Kalavacherla T, Jonker HRA, Richter C, Schwalbe H, Meiler J, Preu J, Michel H, Glaubitz C
(2018) Nat Chem Biol 14: 284-290
MeSH Terms: Animals, HEK293 Cells, Humans, Insecta, Kinins, Ligands, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Docking Simulation, Mutation, Peptides, Protein Binding, Protein Domains, Protein Structure, Secondary, Receptor, Bradykinin B1, Receptor, Bradykinin B2, Receptors, G-Protein-Coupled, Sf9 Cells, Signal Transduction, Static Electricity
Show Abstract · Added March 17, 2018
G-protein-coupled receptors (GPCRs) are the most important signal transducers in higher eukaryotes. Despite considerable progress, the molecular basis of subtype-specific ligand selectivity, especially for peptide receptors, remains unknown. Here, by integrating DNP-enhanced solid-state NMR spectroscopy with advanced molecular modeling and docking, the mechanism of the subtype selectivity of human bradykinin receptors for their peptide agonists has been resolved. The conserved middle segments of the bound peptides show distinct conformations that result in different presentations of their N and C termini toward their receptors. Analysis of the peptide-receptor interfaces reveals that the charged N-terminal residues of the peptides are mainly selected through electrostatic interactions, whereas the C-terminal segments are recognized via both conformations and interactions. The detailed molecular picture obtained by this approach opens a new gateway for exploring the complex conformational and chemical space of peptides and peptide analogs for designing GPCR subtype-selective biochemical tools and drugs.
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20 MeSH Terms
Building collagen IV smart scaffolds on the outside of cells.
Brown KL, Cummings CF, Vanacore RM, Hudson BG
(2017) Protein Sci 26: 2151-2161
MeSH Terms: Amino Acid Motifs, Amino Acid Oxidoreductases, Animals, Antigens, Neoplasm, Basement Membrane, Collagen Type IV, Eukaryotic Cells, Extracellular Matrix, Gene Expression Regulation, Humans, Peroxidases, Protein Interaction Domains and Motifs, Protein Multimerization, Protein Structure, Secondary, Protein Subunits, Receptors, Interleukin-1
Show Abstract · Added November 2, 2017
Collagen IV scaffolds assemble through an intricate pathway that begins intracellularly and is completed extracellularly. Multiple intracellular enzymes act in concert to assemble collagen IV protomers, the building blocks of collagen IV scaffolds. After being secreted from cells, protomers are activated to initiate oligomerization, forming insoluble networks that are structurally reinforced with covalent crosslinks. Within these networks, embedded binding sites along the length of the protomer lead to the "decoration" of collagen IV triple helix with numerous functional molecules. We refer to these networks as "smart" scaffolds, which as a component of the basement membrane enable the development and function of multicellular tissues in all animal phyla. In this review, we present key molecular mechanisms that drive the assembly of collagen IV smart scaffolds.
© 2017 The Protein Society.
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16 MeSH Terms
Membrane protein contact and structure prediction using co-evolution in conjunction with machine learning.
Teixeira PL, Mendenhall JL, Heinze S, Weiner B, Skwark MJ, Meiler J
(2017) PLoS One 12: e0177866
MeSH Terms: Algorithms, Amino Acid Sequence, Humans, Machine Learning, Membrane Proteins, Models, Molecular, Protein Folding, Protein Structure, Secondary
Show Abstract · Added March 17, 2018
De novo membrane protein structure prediction is limited to small proteins due to the conformational search space quickly expanding with length. Long-range contacts (24+ amino acid separation)-residue positions distant in sequence, but in close proximity in the structure, are arguably the most effective way to restrict this conformational space. Inverse methods for co-evolutionary analysis predict a global set of position-pair couplings that best explain the observed amino acid co-occurrences, thus distinguishing between evolutionarily explained co-variances and these arising from spurious transitive effects. Here, we show that applying machine learning approaches and custom descriptors improves evolutionary contact prediction accuracy, resulting in improvement of average precision by 6 percentage points for the top 1L non-local contacts. Further, we demonstrate that predicted contacts improve protein folding with BCL::Fold. The mean RMSD100 metric for the top 10 models folded was reduced by an average of 2 Å for a benchmark of 25 membrane proteins.
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8 MeSH Terms
Differential manipulation of arrestin-3 binding to basal and agonist-activated G protein-coupled receptors.
Prokop S, Perry NA, Vishnivetskiy SA, Toth AD, Inoue A, Milligan G, Iverson TM, Hunyady L, Gurevich VV
(2017) Cell Signal 36: 98-107
MeSH Terms: Amino Acid Sequence, Animals, Arrestins, COS Cells, Cattle, Cercopithecus aethiops, Conserved Sequence, HEK293 Cells, Humans, Lysine, Mutant Proteins, Mutation, Protein Binding, Protein Structure, Secondary, Receptors, G-Protein-Coupled, Rhodopsin
Show Abstract · Added March 14, 2018
Non-visual arrestins interact with hundreds of different G protein-coupled receptors (GPCRs). Here we show that by introducing mutations into elements that directly bind receptors, the specificity of arrestin-3 can be altered. Several mutations in the two parts of the central "crest" of the arrestin molecule, middle-loop and C-loop, enhanced or reduced arrestin-3 interactions with several GPCRs in receptor subtype and functional state-specific manner. For example, the Lys139Ile substitution in the middle-loop dramatically enhanced the binding to inactive M muscarinic receptor, so that agonist activation of the M did not further increase arrestin-3 binding. Thus, the Lys139Ile mutation made arrestin-3 essentially an activation-independent binding partner of M, whereas its interactions with other receptors, including the β-adrenergic receptor and the D and D dopamine receptors, retained normal activation dependence. In contrast, the Ala248Val mutation enhanced agonist-induced arrestin-3 binding to the β-adrenergic and D dopamine receptors, while reducing its interaction with the D dopamine receptor. These mutations represent the first example of altering arrestin specificity via enhancement of the arrestin-receptor interactions rather than selective reduction of the binding to certain subtypes.
Copyright © 2017. Published by Elsevier Inc.
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2 Members
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16 MeSH Terms
Structural insight for chain selection and stagger control in collagen.
Boudko SP, Bächinger HP
(2016) Sci Rep 6: 37831
MeSH Terms: Amino Acid Sequence, Collagen Type IX, Humans, Models, Molecular, Protein Binding, Protein Domains, Protein Folding, Protein Multimerization, Protein Structure, Secondary
Show Abstract · Added November 2, 2017
Collagen plays a fundamental role in all known metazoans. In collagens three polypeptides form a unique triple-helical structure with a one-residue stagger to fit every third glycine residue in the inner core without disturbing the poly-proline type II helical conformation of each chain. There are homo- and hetero-trimeric types of collagen consisting of one, two or three distinct chains. Thus there must be mechanisms that control composition and stagger during collagen folding. Here, we uncover the structural basis for both chain selection and stagger formation of a collagen molecule. Three distinct chains (α1, α2 and α3) of the non-collagenous domain 2 (NC2) of type IX collagen are assembled to guide triple-helical sequences in the leading, middle and trailing positions. This unique domain opens the door for generating any fragment of collagen in its native composition and stagger.
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9 MeSH Terms