6azp
A Structurally Dynamic N-terminal Region Drives Function of the Staphylococcal Peroxidase Inhibitor (SPIN)
Structural highlights
DiseasePERM_HUMAN Defects in MPO are the cause of myeloperoxidase deficiency (MPOD) [MIM:254600. A disorder characterized by decreased myeloperoxidase activity in neutrophils and monocytes that results in disseminated candidiasis.[1] [2] [3] [4] [5] FunctionPERM_HUMAN Part of the host defense system of polymorphonuclear leukocytes. It is responsible for microbicidal activity against a wide range of organisms. In the stimulated PMN, MPO catalyzes the production of hypohalous acids, primarily hypochlorous acid in physiologic situations, and other toxic intermediates that greatly enhance PMN microbicidal activity. Publication Abstract from PubMedThe heme-containing enzyme myeloperoxidase (MPO) is critical for optimal antimicrobial activity of human neutrophils. We recently discovered that the bacterium Staphylococcus aureus expresses a novel immune evasion protein, called SPIN, that binds tightly to MPO, inhibits MPO activity, and contributes to bacterial survival following phagocytosis. A co-crystal structure of SPIN bound to MPO suggested that SPIN blocks substrate access to the catalytic heme by inserting an N-terminal beta-hairpin into the MPO active site channel. Here, we describe a series of experiments that more completely define the structure/function relationships of SPIN. Whereas the SPIN N-terminus adopts a beta-hairpin confirmation upon binding to MPO, solution NMR studies presented here are consistent with this region of SPIN being dynamically structured in the unbound state. Curiously, while the N-terminal beta-hairpin of SPIN accounts for ~55% of the buried surface area in the SPIN/MPO complex, its deletion did not significantly change the affinity of SPIN for MPO but did eliminate the ability of SPIN to inhibit MPO. The flexible nature of the SPIN N-terminus rendered it susceptible to proteolytic degradation by a series of chymotrypsin-like proteases found within neutrophil granules, thereby abrogating SPIN activity. Degradation of SPIN was prevented by the S. aureus immune evasion protein Eap, which acts as a selective inhibitor of neutrophil serine proteases. Together, these studies provide insight into MPO inhibition by SPIN and suggest possible functional synergy between two distinct classes of S. aureus immune evasion proteins. A Structurally Dynamic N-terminal Region Drives Function of the Staphylococcal Peroxidase Inhibitor (SPIN).,de Jong NWM, Ploscariu NT, Ramyar KX, Garcia BL, Herrera AI, Prakash O, Katz BB, Leidal KG, Nauseef WM, van Kessel KPM, van Strijp JAG, Geisbrecht BV J Biol Chem. 2018 Jan 5. pii: RA117.000134. doi: 10.1074/jbc.RA117.000134. PMID:29306874[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
