Predictions of Cleavability of Calpain Proteolysis by Quantitative Structure-Activity Relationship Analysis Using Newly Determined Cleavage Sites and Catalytic Efficiencies of an Oligopeptide Array.

Molecular & Cellular Proteomics : MCP
Fumiko Shinkai-OuchiHiroyuki Sorimachi

Abstract

Calpains are intracellular Ca(2+)-regulated cysteine proteases that are essential for various cellular functions. Mammalian conventional calpains (calpain-1 and calpain-2) modulate the structure and function of their substrates by limited proteolysis. Thus, it is critically important to determine the site(s) in proteins at which calpains cleave. However, the calpains' substrate specificity remains unclear, because the amino acid (aa) sequences around their cleavage sites are very diverse. To clarify calpains' substrate specificities, 84 20-mer oligopeptides, corresponding to P10-P10' of reported cleavage site sequences, were proteolyzed by calpains, and the catalytic efficiencies (kcat/Km) were globally determined by LC/MS. This analysis revealed 483 cleavage site sequences, including 360 novel ones. Thekcat/Kms for 119 sites ranged from 12.5-1,710 M(-1)s(-1) Although most sites were cleaved by both calpain-1 and -2 with a similarkcat/Km, sequence comparisons revealed distinct aa preferences at P9-P7/P2/P5'. The aa compositions of the novel sites were not statistically different from those of previously reported sites as a whole, suggesting calpains have a strict implicit rule for sequence specificity, and that the limited prot...Continue Reading

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Citations

Nov 12, 2016·Nature Reviews. Drug Discovery·Yasuko OnoHiroyuki Sorimachi
Mar 2, 2018·Current Drug Discovery Technologies·Elaheh Kashani-AminAzadeh Ebrahim-Habibi
Apr 1, 2017·BMC Bioinformatics·Wei-Sheng TienKun-Pin Wu
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Aug 18, 2021·Experimental Eye Research·Mackenzie D MartinRaquel L Lieberman
Dec 11, 2021·Frontiers in Cell and Developmental Biology·Océane BallouheyMarc Bartoli

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