Structures of neutrophil serine protease 4 reveal an unusual mechanism of substrate recognition by a trypsin-fold protease.

摘要: Summary Trypsin-fold proteases, the largest mammalian protease family, are classified by their primary substrate specificity into one of three categories, trypsin-like, chymotrypsin-like, and elastase-like, based on key structural features active site. However, recently discovered neutrophil serine 4 (NSP4, also known as PRSS57) presents a paradox: NSP4 exhibits trypsin-like for cleaving substrates after arginine residues, but it bears elastase-like determining residues in Here we show that has fully occluded S1 pocket P1-arginine adopts noncanonical "up" conformation stabilized solvent-exposed H-bond network. This uncommon arrangement, conserved all orthologs, enables to process both well post-translationally modified such methylarginine citrulline. These findings establish distinct paradigm recognition trypsin-fold provide insights function NSP4.