Cotranslational protein assembly imposes evolutionary constraints on homomeric proteins

Nat Struct Mol Biol. 2018 Mar;25(3):279-288. doi: 10.1038/s41594-018-0029-5. Epub 2018 Feb 12.

Abstract

Cotranslational protein folding can facilitate rapid formation of functional structures. However, it can also cause premature assembly of protein complexes, if two interacting nascent chains are in close proximity. By analyzing known protein structures, we show that homomeric protein contacts are enriched toward the C termini of polypeptide chains across diverse proteomes. We hypothesize that this is the result of evolutionary constraints for folding to occur before assembly. Using high-throughput imaging of protein homomers in Escherichia coli and engineered protein constructs with N- and C-terminal oligomerization domains, we show that, indeed, proteins with C-terminal homomeric interface residues consistently assemble more efficiently than those with N-terminal interface residues. Using in vivo, in vitro and in silico experiments, we identify features that govern successful assembly of homomers, which have implications for protein design and expression optimization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Evolution, Molecular
  • Models, Molecular
  • Molecular Chaperones / metabolism
  • Multiprotein Complexes / chemistry*
  • Protein Biosynthesis*
  • Protein Domains
  • Protein Engineering
  • Protein Folding
  • Protein Multimerization*
  • Protein Subunits / biosynthesis*
  • Protein Subunits / chemistry
  • RNA, Messenger / metabolism
  • Ribosomes / metabolism
  • Solubility

Substances

  • Molecular Chaperones
  • Multiprotein Complexes
  • Protein Subunits
  • RNA, Messenger