Journal
BIOCHEMISTRY
Volume 56, Issue 34, Pages 4568-4577Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.biochem.7b00357
Keywords
-
Categories
Funding
- National Institutes of Health [GM080532]
Ask authors/readers for more resources
Unregulated, particularly suppressed programmed cell death is one of the distinguishing features of many cancer cells. The cysteine protease caspase-6, one of the executioners of apoptotic cell death, plays a crucial role in regulation of apoptosis. Several somatic mutations in the CASP6 gene in tumor tissues have been reported. This work explores the effect of CASP6 tumor-associated mutations on the catalytic efficiency and structure of caspase-6. In general, these mutations showed decreased overall rates of catalytic turnover. Mutations within 8 A of the substrate-binding pocket of caspase-6 were found to be the most catalytically deactivating. Notably, the R259H substitution decreased activity by 457-fold. This substitution disrupts the cation-pi stacking interaction between Arg-259 and Trp-227, which is indispensable for proper assembly of the substrate-binding loops in caspase-6. Sequence conservation analysis at the homologous position across the caspase family suggests a role for this cation-pi stacking in the catalytic function of caspases generally. These data suggest that caspase-6 deactivating mutations may contribute to multifactorial carcinogenic transformations.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available