Genomes and Genes
amino acid substitution
Summary: The naturally occurring or experimentally induced replacement of one or more AMINO ACIDS in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish, enhance, or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties.
- Sommese R, Sung J, Nag S, Sutton S, Deacon J, Choe E, et al. Molecular consequences of the R453C hypertrophic cardiomyopathy mutation on human ?-cardiac myosin motor function. Proc Natl Acad Sci U S A. 2013;110:12607-12 pubmed publisher..Loaded in vitro motility assay confirms that the net force in the ensemble is indeed increased. Overall, this study suggests that the R453C mutation should result in a hypercontractile state in the heart muscle. ..
- Batra V, Perera L, Lin P, Shock D, Beard W, Pedersen L, et al. Amino acid substitution in the active site of DNA polymerase ? explains the energy barrier of the nucleotidyl transfer reaction. J Am Chem Soc. 2013;135:8078-88 pubmed publisher..The charge reorganization is mediated by the catalytic magnesium ion in the active site. ..
- Ghosh B, Satyshur K, Czajkowski C. Propofol binding to the resting state of the gloeobacter violaceus ligand-gated ion channel (GLIC) induces structural changes in the inter- and intrasubunit transmembrane domain (TMD) cavities. J Biol Chem. 2013;288:17420-31 pubmed publisher..Propofol-induced motions in the intersubunit cavity were distinct from motions associated with channel activation, indicating propofol stabilizes a novel closed state...
- Paananen A, Ylipaasto P, Smura T, Lempinen M, Galama J, Roivainen M. A single amino acid substitution in viral VP1 protein alters the lytic potential of clone-derived variants of echovirus 9 DM strain in human pancreatic islets. J Med Virol. 2013;85:1267-73 pubmed publisher..lytic capabilities of these clone-derived viruses in human pancreatic islets were modified by a single amino acid substitution (T81A) in the capsid protein VP1...
- Pidala J, Wang T, Haagenson M, Spellman S, Askar M, Battiwalla M, et al. Amino acid substitution at peptide-binding pockets of HLA class I molecules increases risk of severe acute GVHD and mortality. Blood. 2013;122:3651-8 pubmed publisher..We studied the independent impact of amino acid substitution (AAS) at peptide-binding positions 9, 99, 116, and 156, and killer immunoglobulin-like receptor binding ..
- Rothwell S, Stansfeld P, Bragg L, Verkhratsky A, North R. Direct gating of ATP-activated ion channels (P2X2 receptors) by lipophilic attachment at the outer end of the second transmembrane domain. J Biol Chem. 2014;289:618-26 pubmed publisher..The results are consistent with the channel opening mechanism proposed on the basis of closed and open crystal structures and permit the refinement of the position of the TMs within the bilayer. ..
- Kim S, Zhao H, Hardikar S, Singh A, Goodell M, Chen T. A DNMT3A mutation common in AML exhibits dominant-negative effects in murine ES cells. Blood. 2013;122:4086-9 pubmed publisher..Furthermore, expression of Dnmt3a R878H in ES cells containing endogenous Dnmt3a or Dnmt3b induces hypomethylation. These results suggest that the DNMT3A R882 mutations, in addition to being hypomorphic, have dominant-negative effects. ..
- Dejesus E, Kieft R, Albright B, Stephens N, Hajduk S. A single amino acid substitution in the group 1 Trypanosoma brucei gambiense haptoglobin-hemoglobin receptor abolishes TLF-1 binding. PLoS Pathog. 2013;9:e1003317 pubmed publisher..These findings suggest that the single substitution present in the TbgHpHbR directly contributes to the reduced uptake and resistance to TLF-1 seen in these important human pathogens...
- Upadhyay A, Stehling O, Panayiotou C, Rösser R, Lill R, Overby A. Cellular requirements for iron-sulfur cluster insertion into the antiviral radical SAM protein viperin. J Biol Chem. 2017;292:13879-13889 pubmed publisher..Collectively, viperin maturation represents a novel CIA pathway with a minimal requirement of the CIA-targeting factors and represents a new paradigm for the insertion of the Fe/S cofactor into a radical SAM protein. ..
- Pattabiraman G, Panchal R, Medvedev A. The R753Q polymorphism in Toll-like receptor 2 (TLR2) attenuates innate immune responses to mycobacteria and impairs MyD88 adapter recruitment to TLR2. J Biol Chem. 2017;292:10685-10695 pubmed publisher..smegmatis. ..
- Sarma P, Dutta D, Mirza Z, Saikia K, Baishya B. [Point mutations in the DNA binding domain of p53 contribute to glioma progression and poor prognosis]. Mol Biol (Mosk). 2017;51:334-341 pubmed publisher..In high grade glioma, recurrent TP53 point mutations may be the key to tumor progression, thus, emphasizing their significance in gliomagenesis. ..
- Tomasco I, Boullosa N, Hoffmann F, Lessa E. Molecular adaptive convergence in the Î±-globin gene in subterranean octodontid rodents. Gene. 2017;628:275-280 pubmed publisher..These results suggest some adaptive changes associated to fossoriality, but not strictly to life underground. ..
- Heirbaut M, Lermyte F, Martin E, Beelen S, Sobott F, Strelkov S, et al. Specific sequences in the N-terminal domain of human small heat-shock protein HSPB6 dictate preferential hetero-oligomerization with the orthologue HSPB1. J Biol Chem. 2017;292:9944-9957 pubmed publisher..In conclusion, the disordered NTD of HSPB6 helps regulate the size and stability of hetero-oligomeric complexes, indicating that terminal sHSP regions define the assembly properties of these proteins. ..
- Zhao L, Fan J, Xia S, Pan Y, Liu S, Qian G, et al. HMG-CoA synthase 1 is a synthetic lethal partner of BRAFV600E in human cancers. J Biol Chem. 2017;292:10142-10152 pubmed publisher..We conclude that the ketogenic HMGCS1-HMGCL-acetoacetate axis may represent a promising therapeutic target for managing BRAFV600E-positive human cancers. ..
- Rathore U, Saha P, Kesavardhana S, Kumar A, Datta R, Devanarayanan S, et al. Glycosylation of the core of the HIV-1 envelope subunit protein gp120 is not required for native trimer formation or viral infectivity. J Biol Chem. 2017;292:10197-10219 pubmed publisher..In conclusion, these results clarify the role of core gp120 glycosylation and illustrate a general method for designing glycan-free folded protein derivatives. ..
- Lin R, Nie J, Ren J, Liang R, Li D, Wang P, et al. USP4 interacts and positively regulates IRF8 function via K48-linked deubiquitination in regulatory T cells. FEBS Lett. 2017;591:1677-1686 pubmed publisher..In addition, the deficiency of USP4 alleviated the suppressive function of Treg cells. Taken together, our results suggest that USP4 interacts with and stabilizes IRF8 to promote the suppressive function of Treg cells. ..
- Morimoto T, Mineharu Y, Ono K, Nakatochi M, Ichihara S, Kabata R, et al. Significant association of RNF213 p.R4810K, a moyamoya susceptibility variant, with coronary artery disease. PLoS ONE. 2017;12:e0175649 pubmed publisher..82; 95% confidence interval: 0.87-16.77; p = 0.076). The RNF213 p.R4810K variant appears to be significantly associated with coronary artery disease in the Japanese population. ..
- Glover K, Li Y, Mukhopadhyay S, Leuthner Z, Chakravarthy S, Colbert C, et al. Structural transitions in conserved, ordered Beclin 1 domains essential to regulating autophagy. J Biol Chem. 2017;292:16235-16248 pubmed publisher..e. the CCD or the BARAD). Our findings have important implications for the relative stability of autophagy-inactive and autophagy-active BECN1 complexes. ..
- Boutroux H, David B, Guéguen P, Frange P, Vincenot A, Leverger G, et al. ACTN1-related Macrothrombocytopenia: A Novel Entity in the Progressing Field of Pediatric Thrombocytopenia. J Pediatr Hematol Oncol. 2017;39:e515-e518 pubmed publisher..We identified 11 patients with ACTN1-related macrothrombocytopenia diagnosed through pediatric probands. The aim was to underline the specificities of this entity, especially in children, and bring it to the knowledge of pediatricians. ..
- Zhao H, Wu L, Liu G, Feng H. Single-site substitutions improve cold activity and increase thermostability of the dehairing alkaline protease (DHAP). Biosci Biotechnol Biochem. 2016;80:2480-2485 pubmed..7- and 5.0-fold, respectively, when compared with the thermostability of the wild-type DHAP. Conclusively, an increase in the cold activity and thermostability of a bacterial alkaline protease was achieved by protein engineering. ..
- Patel A, Zhang X, Blumenthal R, Cheng X. Structural basis of human PR/SET domain 9 (PRDM9) allele C-specific recognition of its cognate DNA sequence. J Biol Chem. 2017;292:15994-16002 pubmed publisher..This Arg-Asp conformational switch allows identical ZF modules to recognize different sequences. Our findings illuminate the molecular mechanisms for flexible and conserved binding of human PRDM9 alleles to their cognate DNA sequences. ..
- Bu Q, Li Z, Zhang J, Xu F, Liu J, Liu H. The crystal structure of full-length Sizzled from Xenopus laevis yields insights into Wnt-antagonistic function of secreted Frizzled-related proteins. J Biol Chem. 2017;292:16055-16069 pubmed publisher..In summary, the Sizzled structure provides the first insights into how the CRD and the NTR domains relate to each other for modulating Wnt-antagonistic function of sFRPs. ..
- Lomash R, Sheng N, Li Y, Nicoll R, Roche K. Phosphorylation of the kainate receptor (KAR) auxiliary subunit Neto2 at serine 409 regulates synaptic targeting of the KAR subunit GluK1. J Biol Chem. 2017;292:15369-15377 pubmed publisher..These results support a molecular mechanism by which Neto2 phosphorylation at Ser-409 helps restrict GluK1 targeting to the synapse. ..
- Ko B, Paucar D, Halmos B. EGFR T790M: revealing the secrets of a gatekeeper. Lung Cancer (Auckl). 2017;8:147-159 pubmed publisher..cancers, the development of a dominant and frequent resistance mechanism through a threonine-methionine amino acid substitution at position 790 (T790M) of EGFR has limited the long-term efficacy of these targeted therapies...
- Vienneau Hathaway J, Brassfield E, Lane A, Collin M, Correa Garhwal S, Clarke T, et al. Duplication and concerted evolution of MiSp-encoding genes underlie the material properties of minor ampullate silks of cobweb weaving spiders. BMC Evol Biol. 2017;17:78 pubmed publisher..Our sequences also provide templates for recombinant silk proteins with tailored properties. ..
- Hall C, Lytle B, Jensen D, Hoff J, Peterson F, Volkman B, et al. Structure and Dimerization of IreB, a Negative Regulator of Cephalosporin Resistance in Enterococcus faecalis. J Mol Biol. 2017;429:2324-2336 pubmed publisher..Hence, these studies provide new insights into the structure and function of a widely conserved protein of unknown function that is an important regulator of antimicrobial resistance in E. faecalis. ..
- Oda T, Hirabayashi H, Shikauchi G, Takamura R, Hiraga K, Minami H, et al. Structural basis of autoinhibition and activation of the DNA-targeting ADP-ribosyltransferase pierisin-1. J Biol Chem. 2017;292:15445-15455 pubmed publisher..Our study provides a structural basis for the DNA-acceptor specificity of pierisin-1 and reveals that a self-regulatory mechanism is required for its activity. ..
- Itoh N, Nagai T, Watanabe T, Taki K, Nabeshima T, Kaibuchi K, et al. Valosin-containing protein (VCP) is a novel IQ motif-containing GTPase activating protein 1 (IQGAP1)-interacting protein. Biochem Biophys Res Commun. 2017;493:1384-1389 pubmed publisher..These results suggest that reduction of IQGAP1 and VCP interaction may be associated with the pathophysiology of IBMPFD...
- Hudson B, Hyun S, Thompson D, Lyon A. Phospholipase C?3 Membrane Adsorption and Activation Are Regulated by Its C-Terminal Domains and Phosphatidylinositol 4,5-Bisphosphate. Biochemistry. 2017;56:5604-5614 pubmed publisher..Together, these findings support a model in which multiple elements of PLC? modulate adsorption, distribution, and catalysis at the cell membrane. ..
- Padilla Benavides T, Nasipak B, Paskavitz A, Haokip D, Schnabl J, Nickerson J, et al. Casein kinase 2-mediated phosphorylation of Brahma-related gene 1 controls myoblast proliferation and contributes to SWI/SNF complex composition. J Biol Chem. 2017;292:18592-18607 pubmed publisher..Our results indicate that CK2-mediated phosphorylation of Brg1 regulates myoblast proliferation and provides insight into one mechanism by which composition of the mammalian SWI/SNF enzyme complex is regulated. ..
- Tsai C, Nussinov R. Allostery modulates the beat rate of a cardiac pacemaker. J Biol Chem. 2017;292:6429-6430 pubmed publisher..A multifaceted NMR analysis now demonstrates that this mutant impacts allosteric coupling in domains inside of the cell to change channel activation, providing a mechanistic explanation for phenotypic outcomes. ..
- Revtovich S, Morozova E, Kulikova V, Anufrieva N, Osipova T, Koval V, et al. Crystal structure of mutant form Cys115His of Citrobacter freundii methionine ?-lyase complexed with l-norleucine. Biochim Biophys Acta Proteins Proteom. 2017;1865:1123-1128 pubmed publisher..Analysis of the structure allowed us to suggest the possible reason for the inability of the mutant enzyme to catalyze the physiological reaction. ..
- Hara K, Kashiwagi T, Hamada N, Watanabe H. Basic amino acids in the N-terminal half of the PB2 subunit of influenza virus RNA polymerase are involved in both transcription and replication. J Gen Virol. 2017;98:900-905 pubmed publisher..In the three-dimensional structure of the polymerase, 124R is visible through the NTP tunnel and is located close to the polymerase active site. We propose that 124R plays a key role in promoter binding during RNA synthesis. ..
- Robbins J, Souffrant M, Hamelberg D, Gadda G, Bommarius A. Enzyme-Mediated Conversion of Flavin Adenine Dinucleotide (FAD) to 8-Formyl FAD in Formate Oxidase Results in a Modified Cofactor with Enhanced Catalytic Properties. Biochemistry. 2017;56:3800-3807 pubmed publisher..Thus, this work describes a new enzyme cofactor and provides insight into the little-understood mechanism of enzyme-mediated 8?-flavin modifications. ..
- Kerr H, Wong E, Makou E, Yang Y, Marchbank K, Kavanagh D, et al. Disease-linked mutations in factor H reveal pivotal role of cofactor activity in self-surface-selective regulation of complement activation. J Biol Chem. 2017;292:13345-13360 pubmed publisher..We conclude that CCPs 19 and 20 are critical for efficient CA on self-surfaces but less important for DAA. Exposing CCPs 19 and 20 with PspCN and thus enhancing CA on self-surfaces may reverse deficiencies of some CFH variants. ..
- Ruedas J, Ladner J, Ettinger C, Gummuluru S, Palacios G, Connor J. Spontaneous Mutation at Amino Acid 544 of the Ebola Virus Glycoprotein Potentiates Virus Entry and Selection in Tissue Culture. J Virol. 2017;91: pubmed publisher..Understanding the mechanism behind this mutation can provide insight into functional differences that exist in culture conditions and among ebolavirus glycoproteins. ..
- Rahban M, Salehi N, Saboury A, Hosseinkhani S, Karimi Jafari M, Firouzi R, et al. Histidine substitution in the most flexible fragments of firefly luciferase modifies its thermal stability. Arch Biochem Biophys. 2017;629:8-18 pubmed publisher..Based on our results we conclude that the MD simulation-based rational substitution of histidines by salt-bridge forming residues can modulate conformational dynamics in luciferase and shift its optimal temperature activity. ..
- Grishin D, Pokrovskaya M, Podobed O, Gladilina J, Pokrovsky V, Aleksandrova S, et al. [Prediction of protein thermostability from their primary structure: the current state and development factors]. Biomed Khim. 2017;63:124-131 pubmed publisher..Osoboe vnimanie udeleno prognosticheskomu potentsialu statisticheskikh metodov izucheniia termodinamicheskikh pokazatele? pervichno? struktury belka i otseneny ikh perspektivy. ..
- Cooper P, McClenaghan C, Chen X, Stary Weinzinger A, Nichols C. Conserved functional consequences of disease-associated mutations in the slide helix of Kir6.1 and Kir6.2 subunits of the ATP-sensitive potassium channel. J Biol Chem. 2017;292:17387-17398 pubmed publisher..This raises the possibility that, at least for some CS mutations, sulfonylurea therapy may not prove to be successful and highlights the need for detailed pharmacogenomic analyses of CS mutations. ..
- Bourdin B, Briot J, Tétreault M, Sauve R, Parent L. Negatively charged residues in the first extracellular loop of the L-type CaV1.2 channel anchor the interaction with the CaV?2?1 auxiliary subunit. J Biol Chem. 2017;292:17236-17249 pubmed publisher..2 currents. By stabilizing the first extracellular loop of CaV1.2, CaV?2?1 may up-regulate currents by promoting conformations of the voltage sensor that are associated with the channel's open state. ..
- Wu R, Tsai M, Tsai K, Tian J, Wu J, Wu S, et al. Mutagenesis of Dengue Virus Protein NS2A Revealed a Novel Domain Responsible for Virus-Induced Cytopathic Effect and Interactions between NS2A and NS2B Transmembrane Segments. J Virol. 2017;91: pubmed publisher..These results expand the understanding of flavivirus replication. The knowledge may also facilitate studies of pathogenesis and novel vaccine and antiflaviviral drug development. ..
- Wieczor M, Czub J. How proteins bind to DNA: target discrimination and dynamic sequence search by the telomeric protein TRF1. Nucleic Acids Res. 2017;45:7643-7654 pubmed publisher..Our calculated free energy landscapes reproduce the thermodynamics of sequence-specific binding, while statistical approaches allow for a comprehensive description of intermediate stages of complex formation. ..
- Chilton S, Falbel T, Hromada S, Burton B. A Conserved Metal Binding Motif in the Bacillus subtilis Competence Protein ComFA Enhances Transformation. J Bacteriol. 2017;199: pubmed publisher..We demonstrate that several amino acid motifs conserved among ComFA proteins are important for efficient transformation. This report is the first to demonstrate the functional requirement of an amino-terminal cysteine motif in ComFA. ..
- Gu Y, Chang X, Dai S, Song Q, Zhao H, Lei P. Identification of four novel XPC mutations in two xeroderma pigmentosum complementation group C patients and functional study of XPC Q320X mutant. Gene. 2017;628:162-169 pubmed publisher..Readthrough of PTCs is a new approach to treatment of genetic diseases. We found that aminoglycosides could significantly increase the full length protein expression of Q320X mutant, but NER defects were not rescued in vitro. ..