@article {1421,
	title = {Structural Insights into the Unique Activation Mechanisms of a Non-classical Calpain and Its Disease-Causing Variants.},
	journal = {Cell Rep},
	volume = {30},
	year = {2020},
	month = {2020 Jan 21},
	pages = {881-892.e5},
	abstract = {<p>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\&nbsp;{\r A} 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\&gt;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.</p>
},
	issn = {2211-1247},
	doi = {10.1016/j.celrep.2019.12.077},
	author = {Velez, Gabriel and Sun, Young Joo and Khan, Saif and Yang, Jing and Herrmann, Jonathan and Chemudupati, Teja and MacLaren, Robert E and Gakhar, Lokesh and Wakatsuki, Soichi and Bassuk, Alexander G and Mahajan, Vinit B}
}
