An ancient mechanism of arginine-specific substrate cleavage: what's up with NSP4?

An ancient mechanism of arginine-specific substrate cleavage: what's up with NSP4?
Biochimie. 2019 Apr 01;:
Authors: AhYoung AP, Lin SJ, Gerhardy S, van Lookeren Campagne M, Kirchhofer D
Abstract
The recently discovered neutrophil serine protease 4 (NSP4) is the fourth member of the NSP family, which includes the well-studied neutrophil elastase, proteinase 3 and cathepsin G. Like the other three NSP members, NSP4 is synthesized by myeloid precursors in the bone marrow and, after cleavage of the two-amino acid activation peptide, is stored as an active protease in azurophil granules of neutrophils. Based on its primary amino acid sequence, NSP4 is predicted to have a shallow S1 specificity pocket with elastase-like substrate specificity. However, NSP4 was found to preferentially cleave after an arginine residue. Structural studies resolved this paradox by revealing an unprecedented mechanism of P1-arginine recognition. In contrast to the canonical mechanism in which the P1-arginine residue points down into a deep S1 pocket, the arginine side chain adopts a surface-exposed 'up' conformation in the NSP4 active site. This conformation is stabilized by the Phe190 residue, which serves as a hydrophobic platform for the aliphatic portion of the arginine side chain, and a network of hydrogen bonds between the arginine guanidium group and the NSP4 residues Ser192 and Ser216. This unique configuration allows NSP4 to cleave even after naturall...

Source: Biochimie - March 31, 2019 Category: Biochemistry Authors: AhYoung AP, Lin SJ, Gerhardy S, van Lookeren Campagne M, Kirchhofer D Tags: Biochimie Source Type: research