6P3Q

Calpain-5 (CAPN5) Protease Core (PC)

Summary for 6P3Q

• Entry DOI: 10.2210/pdb6p3q/pdb
• Descriptor: Calpain-5 (1 entity in total)
• Functional Keywords: cystein protease, peptide binding protein, calcium binding protein, protease domain, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 82733.20

Authors

Velez, G.,Sun, Y.J.,Khan, S.,Yang, J.,Koster, H.J.,Lokesh, G.,Mahajan, V. (deposition date: 2019-05-24, release date: 2020-02-05, Last modification date: 2024-04-03)

Primary citation

Velez, G.,Sun, Y.J.,Khan, S.,Yang, J.,Herrmann, J.,Chemudupati, T.,MacLaren, R.E.,Gakhar, L.,Wakatsuki, S.,Bassuk, A.G.,Mahajan, V.B.
Structural Insights into the Unique Activation Mechanisms of a Non-classical Calpain and Its Disease-Causing Variants.
Cell Rep, 30:881-892.e5, 2020

PubMed 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.

PubMed: 31968260
DOI: 10.1016/j.celrep.2019.12.077

Experimental method

X-RAY DIFFRACTION (2.8 Å)