Tumor-Associated Mutations in Caspase-6 Negatively Impact Catalytic Efficiency

Biochemistry. 2017 Aug 29;56(34):4568-4577. doi: 10.1021/acs.biochem.7b00357. Epub 2017 Aug 16.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Substitution
  • Caspase 6 / chemistry*
  • Caspase 6 / genetics
  • Caspase 6 / metabolism
  • Catalytic Domain
  • Humans
  • Mutation, Missense*
  • Neoplasm Proteins / chemistry*
  • Neoplasm Proteins / metabolism
  • Neoplasms / enzymology*
  • Neoplasms / genetics

Substances

  • Neoplasm Proteins
  • CASP6 protein, human
  • Caspase 6