The Unconventional Self-Cleavage of Selenoprotein K

Abstract

Through known association with other proteins, human selenoprotein K (selenok) is currently implicated in the palmitoylation of proteins, degradation of misfolded proteins, innate immune response, and the life cycle of SARS-CoV-2 virus. However, neither the catalytic function of selenoks selenocysteine (Sec), which, curiously, resides in an intrinsically disordered protein segment nor selenoks specific role in these pathways are known to date. This report casts these questions in a new light as it describes that selenok is able -both in vitro and in vivo- to cleave some of its own peptide bonds. The cleavages not only release selenok segments that contain its reactive Sec, but as the specific cleavage sites were identified, they proved to cluster tightly near sites through which selenok interacts with protein partners. Furthermore, it is shown that selenoks cleavage activity is neither restricted to itself nor promiscuous but selectively extends to at least one of its protein partners. Together, selenoks cleavage ability and its features have all hallmarks of a regulatory mechanism that could play a central role in selenoks associations with other proteins and its cellular functions overall.