Protein Quality Control Acts on Folding Intermediates to Shape the Effects of Mutations on Organismal Fitness

Shimon Bershtein, Wanmeng Mu, Adrian W.R. Serohijos, Jingwen Zhou, Eugene I. Shakhnovich

Research output: Contribution to journalArticlepeer-review

111 Scopus citations

Abstract

What are the molecular properties of proteins that fall on the radar of protein quality control (PQC)? Here we mutate the E. coli's gene encoding dihydrofolate reductase (DHFR) and replace it with bacterial orthologous genes to determine how components of PQC modulate fitness effects of these genetic changes. We find that chaperonins GroEL/ES and protease Lon compete for binding to molten globule intermediate of DHFR, resulting in a peculiar symmetry in their action: overexpression of GroEL/ES and deletion of Lon both restore growth of deleterious DHFR mutants and most of the slow-growing orthologous DHFR strains. Kinetic steady-state modeling predicts and experimentation verifies that mutations affect fitness by shifting the flux balance in cellular milieu between protein production, folding, and degradation orchestrated by PQC through the interaction with folding intermediates.

Original languageEnglish
Pages (from-to)133-144
Number of pages12
JournalMolecular Cell
Volume49
Issue number1
DOIs
StatePublished - 10 Jan 2013
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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