title: Calpain silencing by a reversible intrinsic mechanism.
abstract: Uncontrolled activation of calpain can lead to necrotic cell death and irreversible tissue damage. We have discovered an intrinsic mechanism whereby the autolysis-generated protease core fragment of calpain is inactivated through the inherent instability of a key alpha-helix. This auto-inactivation state was captured by the 1.9 A Ca(2+)-bound structure of the protease core from m-calpain, and sequence alignments suggest that it applies to about half of the calpain isoforms. Intact calpain large subunits are also subject to this inhibition, which can be prevented through assembly of the heterodimers. Other isoforms or their released cores are not silenced by this mechanism and might contribute to calpain patho-physiologies.
authors.affiliation: Department of Biochemistry and the Protein Engineering Network of Centres of Excellence, Queen's University, Kingston, Ontario K7L 3N6, 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: 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; D002154:Calpain / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006868:Hydrolysis; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015183:Restriction Mapping; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D011994:Recombinant Proteins; D002154:Calpain; C449000:m-calpain