title: A Ca(2+) switch aligns the active site of calpain.
abstract: Ca(2+) signaling by calpains leads to controlled proteolysis during processes ranging from cytoskeleton remodeling in mammals to sex determination in nematodes. Deregulated Ca(2+) levels result in aberrant proteolysis by calpains, which contributes to tissue damage in heart and brain ischemias as well as neurodegeneration in Alzheimer's disease. Here we show that activation of the protease core of mu calpain requires cooperative binding of two Ca(2+) atoms at two non-EF-hand sites revealed in the 2.1 A crystal structure. Conservation of the Ca(2+) binding residues defines an ancestral general mechanism of activation for most calpain isoforms, including some that lack EF-hand domains. The protease region is not affected by the endogenous inhibitor, calpastatin, and may contribute to calpain-mediated pathologies when the core is released by autoproteolysis.
authors.affiliation: Department of Biochemistry and the Protein, Engineering Network of Centres of Excellence, Queen's University, Kingston, Ontario, Canada.
authors.forename: Tudor
authors.initials: T
authors.lastname: Moldoveanu
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Hosfield
authors.forename: Daniel
authors.initials: D
authors.lastname: Lim
authors.forename: John S
authors.initials: JS
authors.lastname: Elce
authors.forename: Zongchao
authors.initials: Z
authors.lastname: Jia
authors.forename: Peter L
authors.initials: PL
authors.lastname: Davies
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002154:Calpain / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D051381:Rats; D016415:Sequence Alignment
chemical_list: D020033:Protein Isoforms; D002154:Calpain; D002118:Calcium