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Structural Insights into the Unique Activation Mechanisms of a Non-classical Calpain and Its Disease-Causing Variants.

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.

journal_name

Cell Rep

journal_title

Cell reports

authors

Velez G,Sun YJ,Khan S,Yang J,Herrmann J,Chemudupati T,MacLaren RE,Gakhar L,Wakatsuki S,Bassuk AG,Mahajan VB

doi

10.1016/j.celrep.2019.12.077

subject

Has Abstract

pub_date

2020-01-21 00:00:00

pages

881-892.e5

issue

3

issn

2211-1247

pii

S2211-1247(19)31742-5

journal_volume

30

pub_type

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