Tumor-Associated Mutations in Caspase‑6 Negatively Impact Catalytic Efficiency
journal contributionposted on 2017-07-20, 00:00 authored by Kevin B. Dagbay, Maureen E. Hill, Elizabeth Barrett, Jeanne A. Hardy
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 Å 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−π 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−π stacking in the catalytic function of caspases generally. These data suggest that caspase-6 deactivating mutations may contribute to multifactorial carcinogenic transformations.
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catalytically deactivatingcaspase -6.R 259H substitutioncancer cellsTumor-Associated Mutationssubstrate-binding loopssubstrate-binding pocketcaspase familycaspase -6CASP 6 geneCASP 6 tumor-associated mutationscaspase -6 deactivating mutationsapoptotic cell death8 ÅArg -259tumor tissuescaspase -6. Sequence conservation analysiscell death