| Title | The regulatory mechanism of the caspase 6 pro-domain revealed by crystal structure and biochemical assays |
| Authors | Cao, Qin Wang, Xiao-Jun Li, Lan-Fen Su, Xiao-Dong |
| Affiliation | Peking Univ, Sch Life Sci, State Key Lab Prot & Plant Gene Res, Beijing 100871, Peoples R China. Peking Univ, Sch Life Sci, Biodynam Opt Imaging Ctr BIOPIC, Beijing 100871, Peoples R China. |
| Keywords | MUTANT HUNTINGTIN SELF-ACTIVATION AMINO-ACID IN-VIVO CLEAVAGE DEGENERATION CONFORMATION METHIONINE PROTEINS CASCADE |
| Issue Date | 2014 |
| Publisher | acta crystallographica section d biological crystallography |
| Citation | ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY.2014,70,58-67. |
| 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. |
| URI | http://hdl.handle.net/20.500.11897/342454 |
| ISSN | 0907-4449 |
| DOI | 10.1107/S1399004713024218 |
| Indexed | SCI(E) PubMed |
| Appears in Collections: | 生命科学学院 |
