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

Cell Reports
Gabriel VelezVinit B Mahajan

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.

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Citations

Aug 28, 2020·American Journal of Reproductive Immunology : AJRI·Shinobu GotoMayumi Sugiura-Ogasawara
Feb 6, 2021·Biochimica Et Biophysica Acta. Proteins and Proteomics·Simone SpinozziIsabelle Richard
Feb 20, 2021·Biochimica Et Biophysica Acta. Molecular Cell Research·Yusaku ChukaiTaku Ozaki
Apr 4, 2021·Biochimica Et Biophysica Acta. Molecular Cell Research·Vimala BondadaJames W Geddes
Apr 13, 2021·The Journal of Clinical Investigation·Young Joo SunVinit B Mahajan
Jul 25, 2020·American Journal of Ophthalmology·Angela S LiVinit B Mahajan

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Methods Mentioned

BETA
X-ray
fluorescence resonance
circular dichroism
FRET
protein scattering

Software Mentioned

PRIMUS
FastTree
HIT
XDS
ATSAS
ConSurf
SasTool
DATGNOM
PHENIX
MaxAlign

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