A structurally dynamic N-terminal region drives function of the staphylococcal peroxidase inhibitor (SPIN)

Jong, Nienke W.M. de; Nicoleta, Ploscariu,; Ramyar, Kasra X.; Garcia, Brandon L.; Herrera, Alvaro I.; Prakash, Om; Katz, Benjamin B.; Leidal, Kevin G.; Nauseef, William M.; Kessel, Kok P. M. van; Strijp, Jos A. G. van; Geisbrecht, Brian V.

doi:10.1074/jbc.ra117.000134

Cited by 20 publications

(31 citation statements)

References 49 publications

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“…This latter feature is consistent with solution NMR spectroscopy studies on SPIN, which demonstrated that the N-terminal β-hairpin is actually disordered in the absence of MPO [19, 20]. Nevertheless, the N-terminal residues of SPIN are required for inhibiting MPO activity [19], since the β-hairpin they comprise inserts into the MPO active site cavity and blocks substrate/product exchange [18].…”

Section: Introductionsupporting

confidence: 69%

“…Interestingly, four of these residues (G 39 , L 42 , D 44 , and D 45 ) lie within the N-terminal region of the SPIN protein. Although this region of SPIN- aureus appears to make only minor contributions to SPIN binding of MPO, it is essential for inhibiting MPO enzymatic activity [19]. Thus, the relatively low level of absolute identity within the known MPO-binding site of SPIN suggested that valuable insights might be gained from further structure/function studies on these SPIN homologs.…”

Section: Resultsmentioning

confidence: 99%

“…Whereas the C-terminal 60 amino acids adopt a compact three α-helical bundle fold, the N-terminal 13 residues comprise a unique β-hairpin motif [18]. Subsequent studies showed that the α-helical bundle domain is responsible for driving interaction of SPIN with MPO, while the β-hairpin region makes only minor contributions to SPIN/MPO binding [19]. This latter feature is consistent with solution NMR spectroscopy studies on SPIN, which demonstrated that the N-terminal β-hairpin is actually disordered in the absence of MPO [19, 20].…”

Section: Introductionmentioning

confidence: 99%

“…Subsequent studies showed that the α-helical bundle domain is responsible for driving interaction of SPIN with MPO, while the β-hairpin region makes only minor contributions to SPIN/MPO binding [19]. This latter feature is consistent with solution NMR spectroscopy studies on SPIN, which demonstrated that the N-terminal β-hairpin is actually disordered in the absence of MPO [19, 20]. Nevertheless, the N-terminal residues of SPIN are required for inhibiting MPO activity [19], since the β-hairpin they comprise inserts into the MPO active site cavity and blocks substrate/product exchange [18].…”

Section: Introductionmentioning

confidence: 99%

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Identification and structural characterization of a novel myeloperoxidase inhibitor from Staphylococcus delphini

Nicoleta

Jong

Kessel

et al. 2018

Archives of Biochemistry and Biophysics

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Staphylococcus aureus and related species are highly adapted to their hosts and have evolved numerous strategies to evade the immune system. S. aureus shows resistance to killing following uptake into the phagosome, which suggests that the bacterium evades intracellular killing mechanisms used by neutrophils. We recently discovered an S. aureus protein (SPIN for Staphylococcal Peroxidase INhibitor) that binds to and inhibits myeloperoxidase (MPO), a major player in the oxidative defense of neutrophils. To allow for comparative studies between multiple SPIN sequences, we identified a panel of homologs from species closely related to S. aureus. Characterization of these proteins revealed that SPIN molecules from S. agnetis, S. delphini, S. schleiferi, and S. intermedius all bind human MPO with nanomolar affinities, and that those from S. delphini, S. schleiferi, and S. intermedius inhibit human MPO in a dose-dependent manner. A 2.4 Å resolution co-crystal structure of SPIN-delphini bound to recombinant human MPO allowed us to identify conserved structural features of SPIN proteins, and to propose sequence-dependent physical explanations for why SPIN-aureus binds human MPO with higher affinity than SPIN-delphini. Together, these studies expand our understanding of MPO binding and inhibition by a recently identified component of the staphylococcal innate immune evasion arsenal.

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Section: Introductionsupporting

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification and structural characterization of a novel myeloperoxidase inhibitor from Staphylococcus delphini

Nicoleta

Jong

Kessel

et al. 2018

Archives of Biochemistry and Biophysics

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“…Members of each family have homologs in higher eukaryotes, and the members of the APC superfamily and the MFS also have homologs in prokaryotes. Whole-cell proteome analyses in S. cerevisiae have allowed the determination of the abundance levels for amino acid transporters, which range from tens to tens of thousands of molecules per cell; the collective data were recently unified in a single data set (44). These studies show that high-affinity transporters such as Gap1, Lyp1, and Mup1 are upregulated in minimal media (thousands to tens of thousands per cell) relative to rich (yeast extract-peptonedextrose [YPD]) media (tens to hundreds per cell) (45,46), which is consistent with the known mechanisms of expression regulation (see below).…”

Section: Amino Acid Transporters From Saccharomyces Cerevisiaementioning

confidence: 99%

Regulation of Amino Acid Transport in Saccharomyces cerevisiae

Bianchi

Klooster

Ruiz

et al. 2019

Microbiol Mol Biol Rev

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SUMMARY We review the mechanisms responsible for amino acid homeostasis in Saccharomyces cerevisiae and other fungi. Amino acid homeostasis is essential for cell growth and survival. Hence, the de novo synthesis reactions, metabolic conversions, and transport of amino acids are tightly regulated. Regulation varies from nitrogen pool sensing to control by individual amino acids and takes place at the gene (transcription), protein (posttranslational modification and allostery), and vesicle (trafficking and endocytosis) levels. The pools of amino acids are controlled via import, export, and compartmentalization. In yeast, the majority of the amino acid transporters belong to the APC (amino acid-polyamine-organocation) superfamily, and the proteins couple the uphill transport of amino acids to the electrochemical proton gradient. Although high-resolution structures of yeast amino acid transporters are not available, homology models have been successfully exploited to determine and engineer the catalytic and regulatory functions of the proteins. This has led to a further understanding of the underlying mechanisms of amino acid sensing and subsequent downregulation of transport. Advances in optical microscopy have revealed a new level of regulation of yeast amino acid transporters, which involves membrane domain partitioning. The significance and the interrelationships of the latest discoveries on amino acid homeostasis are put in context.

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Scylla, Charybdis, and navigating antimicrobial action in the neutrophil phagosome

Nauseef

2022

Journal of Leukocyte Biology

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The text extracted from the initial paragraph of a paper coauthored by Zanvil Cohn, one of the pioneers in the study of leukocyte biology, highlights two phenomena that stimulated investigations of innate immunity in the middle of the last century, namely phagocytosis and intracellular antimicrobial activity. Although many features of phagocytosis have been characterized since that time, fundamental aspects of the antimicrobial action of neutrophils remain unknown. The report by Ashby et al. provides a refined and nuanced look at the interface between an ingested microbe, Staphylococcus aureus, and HOCl generated by the myeloperoxidase (MPO)–H2O2–chloride system in neutrophil phagosomes and represents a holistic approach to the analysis of bactericidal mechanisms that recognizes contributions from both phagocyte and its ingested prey.

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A structurally dynamic N-terminal region drives function of the staphylococcal peroxidase inhibitor (SPIN)

Cited by 20 publications

References 49 publications

Identification and structural characterization of a novel myeloperoxidase inhibitor from Staphylococcus delphini

Identification and structural characterization of a novel myeloperoxidase inhibitor from Staphylococcus delphini

Regulation of Amino Acid Transport in Saccharomyces cerevisiae

Scylla, Charybdis, and navigating antimicrobial action in the neutrophil phagosome

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