6bgp

Crystal Structure of Human Calpain-3 Protease Core Mutant-C129A

spinqualitylabelsall models 6bgp, resolution 2.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6bgp is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.75Å Ligands: CA, CL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease CAN3_HUMAN Autosomal recessive limb girdle muscular dystrophy type 2A. The disease is caused by mutations affecting the gene represented in this entry. Function CAN3_HUMAN Calcium-regulated non-lysosomal thiol-protease. Publication Abstract from PubMed Limb-girdle muscular dystrophy type 2a arises from mutations in the Ca(2+)-activated intracellular cysteine protease calpain-3. This calpain isoform is abundant in skeletal muscle and differs from the main isoforms, calpain-1 and -2, in being a homodimer and having two short insertion sequences. The first of these, IS1, interrupts the protease core and must be cleaved for activation and substrate binding. Here, to learn how calpain-3 can be regulated and inhibited, we determined the structures of the calpain-3 protease core with IS1 present or proteolytically excised. To prevent intramolecular IS1 autoproteolysis, we converted the active-site Cys to Ala. Small-angle X-ray scattering (SAXS) analysis of the C129A mutant suggested that IS1 is disordered and mobile enough to occupy several locations. Surprisingly, this was also true for the apo version of this mutant. We therefore concluded that IS1 might have a binding partner in the sarcomere and is unstructured in its absence. After autoproteolytic IS1 removal from the active Cys-129 calpain-3 protease core, we could solve its crystal structures with and without the cysteine protease inhibitors E-64 and leupeptin covalently bound to the active-site cysteine. In each structure, the active state of the protease core was assembled by the cooperative binding of two Ca(2+) ions to the equivalent sites used in calpain-1 and -2. These structures of the calpain-3 active site with residual IS1 and with bound E-64 and leupeptin may help guide the design of calpain-3-specific inhibitors. Structures of human calpain-3 protease core with and without bound inhibitor reveal mechanisms of calpain activation.,Ye Q, Campbell RL, Davies PL J Biol Chem. 2018 Jan 30. pii: RA117.001097. doi: 10.1074/jbc.RA117.001097. PMID:29382717 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Calpain 3D structures

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