期刊
STRUCTURE
卷 22, 期 9, 页码 1333-1340出版社
CELL PRESS
DOI: 10.1016/j.str.2014.07.008
关键词
-
资金
- Department of Energy Office of Science [DE-AC02-05CH11231, DE-AC02-765F00515]
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 of their active site. However, the recently discovered neutrophil serine protease 4 (NSP4, also known as PRSS57) presents a paradox: NSP4 exhibits a trypsin-like specificity for cleaving substrates after arginine residues, but it bears elastase-like specificity determining residues in the active site. Here we show that NSP4 has a fully occluded Si pocket and that the substrate P1-arginine adopts a noncanonical up conformation stabilized by a solvent-exposed H-bond network. This uncommon arrangement, conserved in all NSP4 orthologs, enables NSP4 to process substrates after both arginine as well as post-translationally modified arginine residues, such as methylarginine and citrulline. These findings establish a distinct paradigm for substrate recognition by a trypsin-fold protease and provide insights into the function of NSP4.
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