Sequence-derived structural features driving proteolytic processing

Alexander A. Belushkin, Dmitry V. Vinogradov, Mikhail S. Gelfand, Andrei L. Osterman, Piotr Cieplak, Marat D. Kazanov

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

Proteolytic signaling, or regulated proteolysis, is an essential part of many important pathways such as Notch, Wnt, and Hedgehog. How the structure of the cleaved substrate regions influences the efficacy of proteolytic processing remains underexplored. Here, we analyzed the relative importance in proteolysis of various structural features derived from substrate sequences using a dataset of more than 5000 experimentally verified proteolytic events captured in CutDB. Accessibility to the solvent was recognized as an essential property of a proteolytically processed polypeptide chain. Proteolytic events were found nearly uniformly distributed among three types of secondary structure, although with some enrichment in loops. Cleavages in α-helices were found to be relatively abundant in regions apparently prone to unfolding, while cleavages in β-structures tended to be located at the periphery of β-sheets. Application of the same statistical procedures to proteolytic events divided into separate sets according to the catalytic classes of proteases proved consistency of the results and confirmed that the structural mechanisms of proteolysis are universal. The estimated prediction power of sequence-derived structural features, which turned out to be sufficiently high, presents a rationale for their use in bioinformatic prediction of proteolytic events.

Original languageEnglish
Pages (from-to)42-50
Number of pages9
JournalProteomics
Volume14
Issue number1
DOIs
Publication statusPublished - Jan 2014
Externally publishedYes

Keywords

  • Bioinformatics
  • Cleavage site
  • Limited proteolysis
  • Protease
  • Proteolytic processing
  • Regulated proteolysis

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