4IYR

Crystal structure of full-length caspase-6 zymogen

Summary for 4IYR

• Entry DOI: 10.2210/pdb4iyr/pdb
• Related: 3nr2 3od5 3v6l 3v6m
• Descriptor: Caspase-6 (2 entities in total)
• Functional Keywords: caspase fold, protease, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 69304.88

Authors

Cao, Q.,Wang, X.-J.,Li, L.-F.,Su, X.-D. (deposition date: 2013-01-29, release date: 2014-01-15, Last modification date: 2023-11-08)

Primary citation

Cao, Q.,Wang, X.J.,Li, L.F.,Su, X.D.
The regulatory mechanism of the caspase 6 pro-domain revealed by crystal structure and biochemical assays.
Acta Crystallogr.,Sect.D, 70:58-67, 2014

PubMed Abstract: Caspase 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.

PubMed: 24419379
DOI: 10.1107/S1399004713024218

Experimental method

X-RAY DIFFRACTION (2.697 Å)