3DF0

Calcium-dependent complex between m-calpain and calpastatin

Summary for 3DF0

• Entry DOI: 10.2210/pdb3df0/pdb
• Descriptor: Calpain-2 catalytic subunit, Calpain small subunit 1, Calpastatin, ... (4 entities in total)
• Functional Keywords: protease core domain, penta ef-hand domains, c2-like domain, inhibitor loop-out, hydrolase, membrane, protease, thiol protease, phosphoprotein, protease inhibitor, thiol protease inhibitor
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Cytoplasm : Q07009 Q64537
• Total number of polymer chains: 3
• Total formula weight: 112562.88

Authors

Moldoveanu, T.,Gehring, K.,Green, D.R. (deposition date: 2008-06-11, release date: 2008-11-11, Last modification date: 2023-08-30)

Primary citation

Moldoveanu, T.,Gehring, K.,Green, D.R.
Concerted multi-pronged attack by calpastatin to occlude the catalytic cleft of heterodimeric calpains.
Nature, 456:404-408, 2008

PubMed Abstract: The Ca(2+)-dependent cysteine proteases, calpains, regulate cell migration, cell death, insulin secretion, synaptic function and muscle homeostasis. Their endogenous inhibitor, calpastatin, consists of four inhibitory repeats, each of which neutralizes an activated calpain with exquisite specificity and potency. Despite the physiological importance of this interaction, the structural basis of calpain inhibition by calpastatin is unknown. Here we report the 3.0 A structure of Ca(2+)-bound m-calpain in complex with the first calpastatin repeat, both from rat, revealing the mechanism of exclusive specificity. The structure highlights the complexity of calpain activation by Ca(2+), illustrating key residues in a peripheral domain that serve to stabilize the protease core on Ca(2+) binding. Fully activated calpain binds ten Ca(2+) atoms, resulting in several conformational changes allowing recognition by calpastatin. Calpain inhibition is mediated by the intimate contact with three critical regions of calpastatin. Two regions target the penta-EF-hand domains of calpain and the third occupies the substrate-binding cleft, projecting a loop around the active site thiol to evade proteolysis.

PubMed: 19020622
DOI: 10.1038/nature07353

Experimental method

X-RAY DIFFRACTION (2.95 Å)