Methionine Mistranslation Bypasses the Restraint of the Genetic Code to Generate Mutant Proteins with Distinct Activities

PLoS Genet. 2015 Dec 28;11(12):e1005745. doi: 10.1371/journal.pgen.1005745. eCollection 2015 Dec.


Although mistranslation is commonly believed to be deleterious, recent evidence indicates that mistranslation can be actively regulated and be beneficial in stress response. Methionine mistranslation in mammalian cells is regulated by reactive oxygen species where cells deliberately alter the proteome through incorporating Met at non-Met positions to enhance oxidative stress response. However, it was not known whether specific, mistranslated mutant proteins have distinct activities from the wild-type protein whose sequence is restrained by the genetic code. Here, we show that Met mistranslation with and without Ca(2+) overload generates specific mutant Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) proteins substituting non-Met with Met at multiple locations. Compared to the genetically encoded wild-type CaMKII, specific mutant CaMKIIs can have distinct activation profiles, intracellular localization and enhanced phenotypes. Our results demonstrate that Met-mistranslation, or "Met-scan" can indeed generate mutant proteins in cells that expand the activity profile of the wild-type protein, and provide a molecular mechanism for the role of regulated mistranslation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / chemistry
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Catalytic Domain
  • Genetic Code*
  • HEK293 Cells
  • Humans
  • Methionine / genetics*
  • Molecular Sequence Data
  • Mutation*
  • Protein Biosynthesis*
  • Protein Transport
  • RNA, Transfer, Met / genetics*
  • RNA, Transfer, Met / metabolism


  • RNA, Transfer, Met
  • Methionine
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2