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S. aureus Eap is a polyvalent inhibitor of neutrophil serine proteases.

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Title: S. aureus Eap is a polyvalent inhibitor of neutrophil serine proteases.
Authors: Mishra, Nitin1, Gido, Carson D.1, Herdendorf, Timothy J.1, Hammel, Michal2, Hura, Gregory L.2, Zheng-Qing Fu3,4, Geisbrecht, Brian V.1 geisbrechtb@ksu.edu
Source: Journal of Biological Chemistry. Sep2024, Vol. 300 Issue 9, p1-18. 18p.
Subjects: Leukocyte elastase, Small-angle scattering, X-ray crystallography, Serine proteinases, Protein domains
Abstract: Staphylococcus aureus expresses three high-affinity neutrophil serine protease (NSP) inhibitors known as the extracellular adherence protein domain (EAPs) proteins. Whereas EapH1 and EapH2 are comprised of a single EAP domain, the modular extracellular adherence protein (Eap) from S. aureus strain Mu50 consists of four EAP domains. We recently reported that EapH2 can simultaneously bind and inhibit cathepsin-G (CG) and neutrophil elastase (NE), which are the two most abundant NSPs. This unusual property of EapH2 arises from independent CG and NE-binding sites that lie on opposing faces of its EAP domain. Here we used X-ray crystallography and enzyme assays to show that all four individual domains of Eap (i.e. Eap1, Eap2, Eap3, and Eap4) exhibit an EapH2-like ability to form ternary complexes with CG and NE that inhibit both enzymes simultaneously. We found that Eap1, Eap2, and Eap3 have similar functional profiles insofar as NSP inhibition is concerned but that Eap4 displays an unexpected ability to inhibit two NE enzymes simultaneously. Using X-ray crystallography, we determined that this second NE-binding site in Eap4 arises through the same region of its EAP domain that also comprises its CG-binding site. Interestingly, small angle X-ray scattering data showed that stable tail-to-tail dimers of the NE/Eap4/NE ternary complex exist in solution. This arrangement is compatible with NSP-binding at all available sites in a twodomain fragment of Eap. Together, our work implies that Eap is a polyvalent inhibitor of NSPs. It also raises the possibility that higher-order structures of NSP-bound Eap may have unique functional properties. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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DbLabel: Engineering Source
An: 180141704
AccessLevel: 6
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 0
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  Data: S. aureus Eap is a polyvalent inhibitor of neutrophil serine proteases.
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  Data: <searchLink fieldCode="AR" term="%22Mishra%2C+Nitin%22">Mishra, Nitin</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Gido%2C+Carson+D%2E%22">Gido, Carson D.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Herdendorf%2C+Timothy+J%2E%22">Herdendorf, Timothy J.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Hammel%2C+Michal%22">Hammel, Michal</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Hura%2C+Gregory+L%2E%22">Hura, Gregory L.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Zheng-Qing+Fu%22">Zheng-Qing Fu</searchLink><relatesTo>3,4</relatesTo><br /><searchLink fieldCode="AR" term="%22Geisbrecht%2C+Brian+V%2E%22">Geisbrecht, Brian V.</searchLink><relatesTo>1</relatesTo><i> geisbrechtb@ksu.edu</i>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Biological+Chemistry%22">Journal of Biological Chemistry</searchLink>. Sep2024, Vol. 300 Issue 9, p1-18. 18p.
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  Data: <searchLink fieldCode="DE" term="%22Leukocyte+elastase%22">Leukocyte elastase</searchLink><br /><searchLink fieldCode="DE" term="%22Small-angle+scattering%22">Small-angle scattering</searchLink><br /><searchLink fieldCode="DE" term="%22X-ray+crystallography%22">X-ray crystallography</searchLink><br /><searchLink fieldCode="DE" term="%22Serine+proteinases%22">Serine proteinases</searchLink><br /><searchLink fieldCode="DE" term="%22Protein+domains%22">Protein domains</searchLink>
– Name: Abstract
  Label: Abstract
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  Data: Staphylococcus aureus expresses three high-affinity neutrophil serine protease (NSP) inhibitors known as the extracellular adherence protein domain (EAPs) proteins. Whereas EapH1 and EapH2 are comprised of a single EAP domain, the modular extracellular adherence protein (Eap) from S. aureus strain Mu50 consists of four EAP domains. We recently reported that EapH2 can simultaneously bind and inhibit cathepsin-G (CG) and neutrophil elastase (NE), which are the two most abundant NSPs. This unusual property of EapH2 arises from independent CG and NE-binding sites that lie on opposing faces of its EAP domain. Here we used X-ray crystallography and enzyme assays to show that all four individual domains of Eap (i.e. Eap1, Eap2, Eap3, and Eap4) exhibit an EapH2-like ability to form ternary complexes with CG and NE that inhibit both enzymes simultaneously. We found that Eap1, Eap2, and Eap3 have similar functional profiles insofar as NSP inhibition is concerned but that Eap4 displays an unexpected ability to inhibit two NE enzymes simultaneously. Using X-ray crystallography, we determined that this second NE-binding site in Eap4 arises through the same region of its EAP domain that also comprises its CG-binding site. Interestingly, small angle X-ray scattering data showed that stable tail-to-tail dimers of the NE/Eap4/NE ternary complex exist in solution. This arrangement is compatible with NSP-binding at all available sites in a twodomain fragment of Eap. Together, our work implies that Eap is a polyvalent inhibitor of NSPs. It also raises the possibility that higher-order structures of NSP-bound Eap may have unique functional properties. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
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      – Type: doi
        Value: 10.1016/j.jbc.2024.107627
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      – Code: eng
        Text: English
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      Pagination:
        PageCount: 18
        StartPage: 1
    Subjects:
      – SubjectFull: Leukocyte elastase
        Type: general
      – SubjectFull: Small-angle scattering
        Type: general
      – SubjectFull: X-ray crystallography
        Type: general
      – SubjectFull: Serine proteinases
        Type: general
      – SubjectFull: Protein domains
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    Titles:
      – TitleFull: S. aureus Eap is a polyvalent inhibitor of neutrophil serine proteases.
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            NameFull: Mishra, Nitin
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            NameFull: Gido, Carson D.
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            NameFull: Herdendorf, Timothy J.
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            NameFull: Hammel, Michal
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            NameFull: Hura, Gregory L.
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            NameFull: Zheng-Qing Fu
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            – D: 01
              M: 09
              Text: Sep2024
              Type: published
              Y: 2024
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              Value: 00219258
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              Value: 300
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              Value: 9
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            – TitleFull: Journal of Biological Chemistry
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