Journal
CELL REPORTS
Volume 30, Issue 3, Pages 881-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.12.077
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Funding
- DOE Office of Biological and Environmental Research (BER)
- NIH [R01EY026682, R01EY024665, R01EY025225, R01EY024698, R21AG050437, P30EY026877, F30EYE027986, T32GM007337, P41GM103393, R01HD084422]
- NIHR Oxford Biomedical Research Centre
- DOE BER
- Stanford PRECOURT Institute
- Stanford Child Health Research Institute
- Pediatric Cancer Research Foundation
- NSF Major Research Instrumentation [DBI-1625906]
- DOE Office of Basic Energy Sciences [DE-AC02-76SF00515]
- NIGMS [P41GM103393]
- DOE Office of Science User Facility [DE-AC02-05CH11231]
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Increased calpain activity is linked to neuroinflammation including a heritable retinal disease caused by hyper-activating mutations in the calcium-activated calpain-5 (CAPN5) protease. Although structures for classical calpains are known, the structure of CAPN5, a non-classical calpain, remains undetermined. Here we report the 2.8 angstrom crystal structure of the human CAPN5 protease core (CAPN5-PC). Compared to classical cal pains, CAPN5-PC requires high calcium concentrations for maximal activity. Structure-based phylogenetic analysis and multiple sequence alignment reveal that CAPN5-PC contains three elongated flexible loops compared to its classical counterparts. The presence of a diseasecausing mutation (c.799G>A, p.Gly267Ser) on the unique PC2L2 loop reveals a function in this region for regulating enzymatic activity. This mechanism could be transferred to distant calpains, using synthetic calpain hybrids, suggesting an evolutionary mechanism for fine-tuning calpain function by modifying flexible loops. Further, the open (inactive) conformation of CAPN5-PC provides structural insight into CAPN5-specific residues that can guide inhibitor design.
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