Caspase Domain Duplication During the Evolution of Caspase-16

Area of Science:

• Molecular biology
• Evolutionary biology
• Biochemistry

Background:

• Caspases are crucial proteases in programmed cell death and inflammation.
• Their function relies on a catalytic dyad within a specific protein fold.
• Caspase-16 (CASP16) is an enigmatic caspase family member with limited prior characterization.

Purpose of the Study:

• To investigate the evolutionary history of caspase-16 (CASP16).
• To understand the structural and functional evolution of CASP16 within the mammalian lineage.
• To identify the evolutionary events leading to the pseudogenization of CASP16 in humans.

Main Methods:

• Comparative sequence analysis of CASP16 orthologs across mammalian species.
• Phylogenetic analysis to determine the origin and divergence of CASP16.
• Identification of gene structures and potential mutations in human and primate CASP16.

Main Results:

• CASP16 orthologs are present in placental mammals, marsupials, and monotremes, indicating an origin predating major mammalian clade divergence.
• CASP16 possesses a unique structure with a carboxy-terminal caspase domain and an amino-terminal prodomain resembling a caspase domain.
• The CASP16 prodomain evolved via exon duplication, with catalytic activity lost in the N-terminal domain and retained in the C-terminal domain.
• Murine and human CASP16 are pseudogenes (CASP16P) due to frameshift mutations.
• Chimpanzee CASP16 and other primate CASP16 genes retain intact coding sequences.

Conclusions:

• Caspase-16 exhibits a unique structural organization distinct from other mammalian caspases.
• The pseudogenization of CASP16 in humans represents a significant evolutionary divergence from closely related primates.
• Understanding CASP16 evolution sheds light on the diversification of caspase functions in mammals.