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Synonymous Mutations Can Alter Protein Dimerization Through Localized Interface Misfolding Involving

Pham Dang Lan1, Daniel Allen Nissley2, Ian Sitarik2

  • 1Institute 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.

Journal of Molecular Biology
|February 10, 2024
PubMed
Summary
This summary is machine-generated.

Synonymous mutations alter protein dimerization by creating non-native entanglements during synthesis. These structural changes affect protein stability and function, impacting oligoribonuclease but not ribonuclease T.

Keywords:
co-translational foldingfunctionkineticsmRNAmisfoldingnon-equilibriumprotein folding

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Area of Science:

  • Molecular Biology
  • Biophysics
  • Computational Biology

Background:

  • Synonymous mutations, which do not alter amino acid sequences, can unexpectedly affect protein function.
  • Protein-protein interactions and dimerization are crucial for cellular processes.
  • Understanding how mRNA sequence variations influence protein structure and dynamics is essential.

Purpose of the Study:

  • To investigate the impact of synonymous mutations on the dimerization of two E. coli homodimers: oligoribonuclease and ribonuclease T.
  • To elucidate the molecular mechanisms by which translation speed, influenced by synonymous mutations, affects protein structure and interaction.
  • To explore the role of non-native entanglements in mediating these effects.

Main Methods:

  • In silico synthesis of proteins from wildtype, fastest-, and slowest-translating synonymous mRNAs.
  • Coarse-grain and all-atom molecular dynamics simulations of protein synthesis, post-translational dynamics, and dimerization.
  • Calculation of ensemble-averaged interaction energies between protein dimers.
  • Limited-proteolysis mass spectrometry to validate simulation predictions.

Main Results:

  • Synonymous mutations significantly altered oligoribonuclease dimerization, with interaction energy increasing by 4% and 10% for fastest- and slowest-translating mRNAs, respectively.
  • Ribonuclease T dimerization remained unaffected by synonymous mutations.
  • Non-covalent lasso-entanglements in misfolded states, dependent on translation speed, were identified as the structural origin of altered dimerization.
  • These entangled states act as long-lived kinetic traps, strongly associated with altered dimer conformations.

Conclusions:

  • Synonymous mutations can impact protein structure and stability through translation-dependent formation of non-native entanglements.
  • Altered entanglement at dimer interfaces provides a mechanism for modulating oligomer structure and stability.
  • The observed effects are protein-specific, with oligoribonuclease being sensitive while ribonuclease T is not.