Multiple proteolytic events in caspase-6 self-activation impact conformations of discrete structural regions

Caspases are central players in programmed cell death. Among caspases, caspase-6 is unique for its association with neurological disorders, including Alzheimer's, Huntington's, and Parkinson's diseases. The structural details underlying caspase-6 activation are still limited but are requisites in understanding caspase-6 function. The prodomain and linker play essential roles in caspase function and regulation; however, while the long prodomains in initiator caspases are known, the structures of the short prodomains in executioner caspases remain elusive, despite efforts using crystallography and NMR. Here, we used hydrogen/deuterium exchange MS and revealed two important findings: the prodomain and intersubunit linker are intrinsically disordered, and the presence or absence of these regions results in distinct structural dynamics as procaspase-6 progresses through its proteolytic activation.