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Synonymous Mutations Can Alter Protein Dimerization Through Localized Interface Misfolding Involving Self-entanglements.
Lan, Pham Dang; Nissley, Daniel Allen; Sitarik, Ian; Vu, Quyen V; Jiang, Yang; To, Philip; Xia, Yingzi; Fried, Stephen D; Li, Mai Suan; O'Brien, Edward P.
Afiliación
  • Lan PD; Institute for Computational Sciences and Technology, Ho Chi Minh City, Viet Nam; Faculty of Physics and Engineering Physics, VNUHCM-University of Science, 227, Nguyen Van Cu Street, District 5, Ho Chi Minh City, Viet Nam.
  • Nissley DA; Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA.
  • Sitarik I; Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA.
  • Vu QV; Institute of Physics, Polish Academy of Sciences, 02-668 Warsaw, Poland.
  • Jiang Y; Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA.
  • To P; Department of Chemistry, Johns Hopkins University, Baltimore, MD 21218, USA.
  • Xia Y; Department of Chemistry, Johns Hopkins University, Baltimore, MD 21218, USA.
  • Fried SD; Department of Chemistry, Johns Hopkins University, Baltimore, MD 21218, USA; Thomas C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218, USA.
  • Li MS; Institute for Computational Sciences and Technology, Ho Chi Minh City, Viet Nam; Institute of Physics, Polish Academy of Sciences, 02-668 Warsaw, Poland.
  • O'Brien EP; Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA; Bioinformatics and Genomics Graduate Program, The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA; Institute for Computational and Data Sciences, Pennsylvania S
J Mol Biol ; 436(6): 168487, 2024 03 15.
Article en En | MEDLINE | ID: mdl-38341172
ABSTRACT
Synonymous mutations in messenger RNAs (mRNAs) can reduce protein-protein binding substantially without changing the protein's amino acid sequence. Here, we use coarse-grain simulations of protein synthesis, post-translational dynamics, and dimerization to understand how synonymous mutations can influence the dimerization of two E. coli homodimers, oligoribonuclease and ribonuclease T. We synthesize each protein from its wildtype, fastest- and slowest-translating synonymous mRNAs in silico and calculate the ensemble-averaged interaction energy between the resulting dimers. We find synonymous mutations alter oligoribonuclease's dimer properties. Relative to wildtype, the dimer interaction energy becomes 4% and 10% stronger, respectively, when translated from its fastest- and slowest-translating mRNAs. Ribonuclease T dimerization, however, is insensitive to synonymous mutations. The structural and kinetic origin of these changes are misfolded states containing non-covalent lasso-entanglements, many of which structurally perturb the dimer interface, and whose probability of occurrence depends on translation speed. These entangled states are kinetic traps that persist for long time scales. Entanglements cause altered dimerization energies for oligoribonuclease, as there is a large association (odds ratio 52) between the co-occurrence of non-native self-entanglements and weak-binding dimer conformations. Simulated at all-atom resolution, these entangled structures persist for long timescales, indicating the conclusions are independent of model resolution. Finally, we show that regions of the protein we predict to have changes in entanglement are also structurally perturbed during refolding, as detected by limited-proteolysis mass spectrometry. Thus, non-native changes in entanglement at dimer interfaces is a mechanism through which oligomer structure and stability can be altered.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Membrana Celular / Escherichia coli / Exorribonucleasas / Multimerización de Proteína / Mutación Silenciosa Tipo de estudio: Prognostic_studies Idioma: En Revista: J Mol Biol Año: 2024 Tipo del documento: Article

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Membrana Celular / Escherichia coli / Exorribonucleasas / Multimerización de Proteína / Mutación Silenciosa Tipo de estudio: Prognostic_studies Idioma: En Revista: J Mol Biol Año: 2024 Tipo del documento: Article