4iyr
From Proteopedia
Crystal structure of full-length caspase-6 zymogen
Structural highlights
FunctionCASP6_HUMAN Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves poly(ADP-ribose) polymerase in vitro, as well as lamins. Overexpression promotes programmed cell death. Publication Abstract from PubMedCaspase 6 (CASP6) is a neuron degeneration-related protease and is widely considered to be a potential drug-design target against neurodegenerative diseases such as Huntington's disease and Alzheimer's disease. The N-terminal pro-peptide of CASP6, also referred to as the pro-domain, contains 23 residues and its functional role remains elusive. In this study, the crystal structure of a full-length CASP6 zymogen mutant, proCASP6H121A, was solved. Although the pro-domain was flexible in the crystal, without visible electron density, structural analyses combined with biochemical assays revealed that the pro-domain inhibited CASP6 auto-activation by inhibiting intramolecular cleavage at the intersubunit cleavage site TEVD(193) and also by preventing this site from intermolecular cleavage at low protein concentration through a so-called `suicide-protection' mechanism. Further experiments showed that the length of the pro-domain and the side chain of Asn18 played critical roles in suicide protection. These results disclosed a new inhibitory mechanism of CASP6 and shed light on the pathogenesis and therapeutically relevant study of CASP6-related neurodegenerative diseases. The regulatory mechanism of the caspase 6 pro-domain revealed by crystal structure and biochemical assays.,Cao Q, Wang XJ, Li LF, Su XD Acta Crystallogr D Biol Crystallogr. 2014 Jan;70(Pt 1):58-67. doi:, 10.1107/S1399004713024218. Epub 2013 Dec 24. PMID:24419379[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Cao Q | Li L-F | Su X-D | Wang X-J