Title | Structural Insights into the Unique Activation Mechanisms of a Non-classical Calpain and Its Disease-Causing Variants. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Velez, Gabriel, Sun Young Joo, Khan Saif, Yang Jing, Herrmann Jonathan, Chemudupati Teja, MacLaren Robert E., Gakhar Lokesh, Wakatsuki Soichi, Bassuk Alexander G., and Mahajan Vinit B. |
Journal | Cell Rep |
Volume | 30 |
Issue | 3 |
Pagination | 881-892.e5 |
Date Published | 2020 Jan 21 |
ISSN | 2211-1247 |
Abstract | 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 Å crystal structure of the human CAPN5 protease core (CAPN5-PC). Compared to classical calpains, 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 disease-causing 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. |
DOI | 10.1016/j.celrep.2019.12.077 |
Alternate Journal | Cell Rep |
PubMed ID | 31968260 |