1ziv

From Proteopedia

Revision as of 13:02, 23 January 2008

Catalytic Domain of Human Calpain-9

Overview

Calpains are calcium activated cysteine proteases found throughout the, animal, plant, and fungi kingdoms; 14 isoforms have been described in the, human genome. Calpains have been implicated in multiple models of human, disease; for instance, calpain 1 is activated in the brains of individuals, with Alzheimer's disease, and the digestive tract specific calpain 9 is, down-regulated in gastric cancer cell lines. We have solved the structures, of human calpain 1 and calpain 9 protease cores using crystallographic, methods; both structures have clear implications for the function of, non-catalytic domains of full-length calpains in the calcium-mediated, activation of the enzyme. The structure of minicalpain 1 is similar to, previously solved structures of the protease core. Auto-inhibition in this, system is most likely through rearrangements of a central helical/loop, region near the active site cysteine, which occlude the substrate binding, site. However, the structure of minicalpain 9 indicates that, auto-inhibition in this enzyme is mediated through large intra-domain, movements that misalign the catalytic triad. This disruption is, reminiscent of the full-length inactive calpain conformation. The, structures of the highly conserved, ubiquitously expressed human calpain 1, and the more tissue specific human calpain 9 indicate that although there, are high levels of sequence conservation throughout the calpain family, isolated structures of family members are insufficient to explain the, molecular mechanism of activation for this group of proteins.

About this Structure

1ZIV is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.

Reference

The crystal structures of human calpains 1 and 9 imply diverse mechanisms of action and auto-inhibition., Davis TL, Walker JR, Finerty PJ Jr, Mackenzie F, Newman EM, Dhe-Paganon S, J Mol Biol. 2007 Feb 9;366(1):216-29. Epub 2006 Nov 14. PMID:17157313

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