2ary
Catalytic domain of Human Calpain-1
OverviewOverview
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 StructureAbout this Structure
2ARY is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
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 Page seeded by OCA on Sat May 3 19:24:14 2008
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OCA- Pages with broken file links
- Calpain-1
- Homo sapiens
- Single protein
- Arrowsmith, C.
- Bochkarev, A.
- Davis, T.
- Dhe-Paganon, S.
- Edwards, A.
- Lunin, V.
- Mackenzie, F.
- Newman, E M.
- SGC, Structural Genomics Consortium.
- Sundstrom, M.
- Walker, J R.
- Weigelt, J.
- Calcium-dependent
- Cysteine protease
- Hydrolase,structural genomics consortium
- Papain
- Sgc
- Thiol protease