Molecular Basis for <named-content content-type="genus-species">Bordetella pertussis</named-content> Interference with Complement, Coagulation, Fibrinolytic, and Contact Activation Systems: the Cryo-EM Structure of the Vag8-C1 Inhibitor Complex

ABSTRACT Complement, contact activation, coagulation, and fibrinolysis are serum protein cascades that need strict regulation to maintain human health. Serum glycoprotein, a C1 inhibitor (C1-INH), is a key regulator (inhibitor) of serine proteases of all the above-mentioned pathways. Recently, an au...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Arun Dhillon, Justin C. Deme, Emily Furlong, Dorina Roem, Ilse Jongerius, Steven Johnson, Susan M. Lea
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	Bordetella pertussis immune evasion complement system serpin autotransporters C1-INH Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/089a29c6c6894167ac20a9fe9aa84830
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:089a29c6c6894167ac20a9fe9aa84830
record_format	dspace
spelling	oai:doaj.org-article:089a29c6c6894167ac20a9fe9aa848302021-11-10T18:37:48ZMolecular Basis for <named-content content-type="genus-species">Bordetella pertussis</named-content> Interference with Complement, Coagulation, Fibrinolytic, and Contact Activation Systems: the Cryo-EM Structure of the Vag8-C1 Inhibitor Complex10.1128/mBio.02823-202150-7511https://doaj.org/article/089a29c6c6894167ac20a9fe9aa848302021-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02823-20https://doaj.org/toc/2150-7511ABSTRACT Complement, contact activation, coagulation, and fibrinolysis are serum protein cascades that need strict regulation to maintain human health. Serum glycoprotein, a C1 inhibitor (C1-INH), is a key regulator (inhibitor) of serine proteases of all the above-mentioned pathways. Recently, an autotransporter protein, virulence-associated gene 8 (Vag8), produced by the whooping cough pathogen, Bordetella pertussis, was shown to bind to C1-INH and interfere with its function. Here, we present the structure of the Vag8–C1-INH complex determined using cryo-electron microscopy at a 3.6-Å resolution. The structure shows a unique mechanism of C1-INH inhibition not employed by other pathogens, where Vag8 sequesters the reactive center loop of C1-INH, preventing its interaction with the target proteases. IMPORTANCE The structure of a 10-kDa protein complex is one of the smallest to be determined using cryo-electron microscopy at high resolution. The structure reveals that C1-INH is sequestered in an inactivated state by burial of the reactive center loop in Vag8. By so doing, the bacterium is able to simultaneously perturb the many pathways regulated by C1-INH. Virulence mechanisms such as the one described here assume more importance given the emerging evidence about dysregulation of contact activation, coagulation, and fibrinolysis leading to COVID-19 pneumonia.Arun DhillonJustin C. DemeEmily FurlongDorina RoemIlse JongeriusSteven JohnsonSusan M. LeaAmerican Society for MicrobiologyarticleBordetella pertussisimmune evasioncomplement systemserpinautotransportersC1-INHMicrobiologyQR1-502ENmBio, Vol 12, Iss 2 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Bordetella pertussis immune evasion complement system serpin autotransporters C1-INH Microbiology QR1-502
spellingShingle	Bordetella pertussis immune evasion complement system serpin autotransporters C1-INH Microbiology QR1-502 Arun Dhillon Justin C. Deme Emily Furlong Dorina Roem Ilse Jongerius Steven Johnson Susan M. Lea Molecular Basis for <named-content content-type="genus-species">Bordetella pertussis</named-content> Interference with Complement, Coagulation, Fibrinolytic, and Contact Activation Systems: the Cryo-EM Structure of the Vag8-C1 Inhibitor Complex
description	ABSTRACT Complement, contact activation, coagulation, and fibrinolysis are serum protein cascades that need strict regulation to maintain human health. Serum glycoprotein, a C1 inhibitor (C1-INH), is a key regulator (inhibitor) of serine proteases of all the above-mentioned pathways. Recently, an autotransporter protein, virulence-associated gene 8 (Vag8), produced by the whooping cough pathogen, Bordetella pertussis, was shown to bind to C1-INH and interfere with its function. Here, we present the structure of the Vag8–C1-INH complex determined using cryo-electron microscopy at a 3.6-Å resolution. The structure shows a unique mechanism of C1-INH inhibition not employed by other pathogens, where Vag8 sequesters the reactive center loop of C1-INH, preventing its interaction with the target proteases. IMPORTANCE The structure of a 10-kDa protein complex is one of the smallest to be determined using cryo-electron microscopy at high resolution. The structure reveals that C1-INH is sequestered in an inactivated state by burial of the reactive center loop in Vag8. By so doing, the bacterium is able to simultaneously perturb the many pathways regulated by C1-INH. Virulence mechanisms such as the one described here assume more importance given the emerging evidence about dysregulation of contact activation, coagulation, and fibrinolysis leading to COVID-19 pneumonia.
format	article
author	Arun Dhillon Justin C. Deme Emily Furlong Dorina Roem Ilse Jongerius Steven Johnson Susan M. Lea
author_facet	Arun Dhillon Justin C. Deme Emily Furlong Dorina Roem Ilse Jongerius Steven Johnson Susan M. Lea
author_sort	Arun Dhillon
title	Molecular Basis for <named-content content-type="genus-species">Bordetella pertussis</named-content> Interference with Complement, Coagulation, Fibrinolytic, and Contact Activation Systems: the Cryo-EM Structure of the Vag8-C1 Inhibitor Complex
title_short	Molecular Basis for <named-content content-type="genus-species">Bordetella pertussis</named-content> Interference with Complement, Coagulation, Fibrinolytic, and Contact Activation Systems: the Cryo-EM Structure of the Vag8-C1 Inhibitor Complex
title_full	Molecular Basis for <named-content content-type="genus-species">Bordetella pertussis</named-content> Interference with Complement, Coagulation, Fibrinolytic, and Contact Activation Systems: the Cryo-EM Structure of the Vag8-C1 Inhibitor Complex
title_fullStr	Molecular Basis for <named-content content-type="genus-species">Bordetella pertussis</named-content> Interference with Complement, Coagulation, Fibrinolytic, and Contact Activation Systems: the Cryo-EM Structure of the Vag8-C1 Inhibitor Complex
title_full_unstemmed	Molecular Basis for <named-content content-type="genus-species">Bordetella pertussis</named-content> Interference with Complement, Coagulation, Fibrinolytic, and Contact Activation Systems: the Cryo-EM Structure of the Vag8-C1 Inhibitor Complex
title_sort	molecular basis for <named-content content-type="genus-species">bordetella pertussis</named-content> interference with complement, coagulation, fibrinolytic, and contact activation systems: the cryo-em structure of the vag8-c1 inhibitor complex
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/089a29c6c6894167ac20a9fe9aa84830
work_keys_str_mv	AT arundhillon molecularbasisfornamedcontentcontenttypegenusspeciesbordetellapertussisnamedcontentinterferencewithcomplementcoagulationfibrinolyticandcontactactivationsystemsthecryoemstructureofthevag8c1inhibitorcomplex AT justincdeme molecularbasisfornamedcontentcontenttypegenusspeciesbordetellapertussisnamedcontentinterferencewithcomplementcoagulationfibrinolyticandcontactactivationsystemsthecryoemstructureofthevag8c1inhibitorcomplex AT emilyfurlong molecularbasisfornamedcontentcontenttypegenusspeciesbordetellapertussisnamedcontentinterferencewithcomplementcoagulationfibrinolyticandcontactactivationsystemsthecryoemstructureofthevag8c1inhibitorcomplex AT dorinaroem molecularbasisfornamedcontentcontenttypegenusspeciesbordetellapertussisnamedcontentinterferencewithcomplementcoagulationfibrinolyticandcontactactivationsystemsthecryoemstructureofthevag8c1inhibitorcomplex AT ilsejongerius molecularbasisfornamedcontentcontenttypegenusspeciesbordetellapertussisnamedcontentinterferencewithcomplementcoagulationfibrinolyticandcontactactivationsystemsthecryoemstructureofthevag8c1inhibitorcomplex AT stevenjohnson molecularbasisfornamedcontentcontenttypegenusspeciesbordetellapertussisnamedcontentinterferencewithcomplementcoagulationfibrinolyticandcontactactivationsystemsthecryoemstructureofthevag8c1inhibitorcomplex AT susanmlea molecularbasisfornamedcontentcontenttypegenusspeciesbordetellapertussisnamedcontentinterferencewithcomplementcoagulationfibrinolyticandcontactactivationsystemsthecryoemstructureofthevag8c1inhibitorcomplex
_version_	1718439840183222272

Molecular Basis for <named-content content-type="genus-species">Bordetella pertussis</named-content> Interference with Complement, Coagulation, Fibrinolytic, and Contact Activation Systems: the Cryo-EM Structure of the Vag8-C1 Inhibitor Complex

Ejemplares similares