The functional role of cysteine residues for c-Abl kinase activity

Mol Cell Biochem. 2007 Oct;304(1-2):207-12. doi: 10.1007/s11010-007-9501-y. Epub 2007 Jun 22.

Abstract

S-glutathionylation, the formation of mixed disulfides of glutathione with cysteine residues of proteins, is a broadly observed physiological modification that occurs in response to oxidative stress. Since cysteine residues are particularly susceptible to oxidative modification by reactive oxygen species, S-glutathionylation can protect proteins from irreversible oxidation. In this study, we show that the kinase activity of the non-receptor tyrosine kinase c-Abl is inhibited by in vitro thiol modification; specifically, the cysteine residues of c-Abl are modified by S-glutathionylation and by thiol alkylating agents such as 4-acetamido-4'-maleimidylstilbene-2,2'-disulfonic acid and N-ethylmaleimide. Modification of cysteine residues of c-Abl tyrosine kinase using glutathione disulfide and thiol alkylating agents corresponds to a concomitant loss of kinase activity. We also demonstrate that S-glutathionylation of c-Abl can be reversed using a physiological system involving glutaredoxin and this reversal restores c-Abl kinase activity. To our knowledge, these are the first data to show S-glutathionylation of c-Abl, and this modification may represent a mechanism of regulation of c-Abl kinase activity in cells under oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylating Agents / pharmacology
  • Animals
  • Cysteine / metabolism
  • Cysteine / physiology*
  • Enzyme Activation / drug effects
  • Glutaredoxins / metabolism
  • Glutathione / metabolism
  • Insecta
  • Proto-Oncogene Proteins c-abl / chemistry*
  • Proto-Oncogene Proteins c-abl / metabolism*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism

Substances

  • Alkylating Agents
  • Glutaredoxins
  • Recombinant Proteins
  • Proto-Oncogene Proteins c-abl
  • Glutathione
  • Cysteine