6AZP

A Structurally Dynamic N-terminal Region Drives Function of the Staphylococcal Peroxidase Inhibitor (SPIN)

Summary for 6AZP

• Entry DOI: 10.2210/pdb6azp/pdb
• Descriptor: Myeloperoxidase, Staphylococcal Peroxidase Inhibitor, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: myeloperoxidase, inhibitor, complex, innate immune evasion, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 73849.08

Authors

Ramyar, K.X.,Geisbrecht, B.V. (deposition date: 2017-09-11, release date: 2017-12-27, Last modification date: 2024-11-06)

Primary citation

de Jong, N.W.M.,Ploscariu, N.T.,Ramyar, K.X.,Garcia, B.L.,Herrera, A.I.,Prakash, O.,Katz, B.B.,Leidal, K.G.,Nauseef, W.M.,van Kessel, K.P.M.,van Strijp, J.A.G.,Geisbrecht, B.V.
A structurally dynamic N-terminal region drives function of the staphylococcal peroxidase inhibitor (SPIN).
J. Biol. Chem., 293:2260-2271, 2018

PubMed Abstract: The heme-containing enzyme myeloperoxidase (MPO) is critical for optimal antimicrobial activity of human neutrophils. We recently discovered that the bacterium 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 β-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 β-hairpin confirmation upon binding to MPO, the solution NMR studies presented here are consistent with this region of SPIN being dynamically structured in the unbound state. Curiously, whereas the N-terminal β-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 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 immune evasion proteins.

PubMed: 29306874
DOI: 10.1074/jbc.RA117.000134

Experimental method

X-RAY DIFFRACTION (2.291 Å)