Effect of caspase cleavage-site phosphorylation on proteolysis

József Tözsér, Péter Bagossi, Gábor Zahuczky, Suzanne I. Specht, Eva Majerova, Terry D. Copeland

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Caspases are important mediators of apoptotic cell death. Several cellular protein substrates of caspases contain potential phosphorylation site(s) at the cleavage-site region, and some of these sites have been verified to be phosphorylated. Since phosphorylation may affect substantially the substrate susceptibility towards proteolysis, phosphorylated, non-phosphorylated and substituted oligopeptides representing such cleavage sites were studied as substrates of apoptotic caspases 3, 7 and 8. Peptides containing phosphorylated serine residues at P4 and P1′ positions were found to be substantially less susceptible towards proteolysis as compared with the serine-containing analogues, while phosphoserine at P3 did not have a substantial effect. P1 serine as well as P1-phosphorylated, serine-containing analogues of an oligopeptide representing the poly(ADP-ribose) polymerase cleavage site of caspase-3 were not hydrolysed by any of these enzymes, whereas the P1 aspartate-containing peptides were efficiently hydrolysed. These findings were interpreted with the aid of molecular modelling. Our results suggest that cleavage-site phosphorylation in certain positions could be disadvantageous or detrimental with respect to cleavability by caspases. Cleavage-site phosphorylation may therefore provide a regulatory mechanism to protect substrates from caspase-mediated degradation.

Original languageEnglish
Pages (from-to)137-143
Number of pages7
JournalBiochemical Journal
Volume372
Issue number1
DOIs
Publication statusPublished - May 15 2003

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Keywords

  • Caspase-3
  • Caspase-7
  • Caspase-8
  • Cleavage site
  • Oligopeptide
  • Substrate specificity

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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