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gC1qR/C1qBP/HABP-1: Structural Analysis of the Trimeric Core Region, Interactions With a Novel Panel of Monoclonal Antibodies, and Their Influence on Binding to FXII

The protein gC1qR/C1qBP/HABP-1 plays an essential role in mitochondrial biogenesis, but becomes localized at the cellular surface in numerous pathophysiological states. When this occurs on endothelial cells, surface-exposed gC1qR activates the classical pathway of complement. It also promotes assemb...

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Autores principales: Zhang, Ying, Vontz, Alexander J., Kallenberger, Ethan M., Xu, Xin, Ploscariu, Nicoleta T., Ramyar, Kasra X., Garcia, Brandon L., Ghebrehiwet, Berhane, Geisbrecht, Brian V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9294231/
https://www.ncbi.nlm.nih.gov/pubmed/35865516
http://dx.doi.org/10.3389/fimmu.2022.887742
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author Zhang, Ying
Vontz, Alexander J.
Kallenberger, Ethan M.
Xu, Xin
Ploscariu, Nicoleta T.
Ramyar, Kasra X.
Garcia, Brandon L.
Ghebrehiwet, Berhane
Geisbrecht, Brian V.
author_facet Zhang, Ying
Vontz, Alexander J.
Kallenberger, Ethan M.
Xu, Xin
Ploscariu, Nicoleta T.
Ramyar, Kasra X.
Garcia, Brandon L.
Ghebrehiwet, Berhane
Geisbrecht, Brian V.
author_sort Zhang, Ying
collection PubMed
description The protein gC1qR/C1qBP/HABP-1 plays an essential role in mitochondrial biogenesis, but becomes localized at the cellular surface in numerous pathophysiological states. When this occurs on endothelial cells, surface-exposed gC1qR activates the classical pathway of complement. It also promotes assembly of a multi-protein complex comprised of coagulation factor XII (FXII), pre-kallikrein (PK), and high-molecular weight kininogen (HMWK) that activates the contact system and the kinin-generating system. Since surface-exposed gC1qR triggers intravascular inflammatory pathways, there is interest in identifying molecules that block gC1qR function. Here we further that objective by reporting the outcome of a structure/function investigation of gC1qR, its interactions with FXII, and the impact of a panel of monoclonal anti-gC1qR antibodies on FXII binding to gC1qR. Although deletion mutants have been used extensively to assess gC1qR function, none of these proteins have been characterized structurally. To that end, we determined a 2.2 Å resolution crystal structure of a gC1qR mutant lacking both of its acidic loops, but which retained nanomolar-affinity binding to FXII and FXIIa. This structure revealed that the trimeric gC1qR assembly was maintained despite loss of roughly thirty residues. Characterization of a novel panel of anti-gC1qR monoclonal antibodies identified several with biochemical properties distinct from previously described antibodies, as well as one which bound to the first acidic loop of gC1qR. Intriguingly, we found that each of these antibodies could partly inhibit binding of FXII and FXIIa to gC1qR. Based on these results and previously published studies, we offer new perspectives for developing gC1qR inhibitors.
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spelling pubmed-92942312022-07-20 gC1qR/C1qBP/HABP-1: Structural Analysis of the Trimeric Core Region, Interactions With a Novel Panel of Monoclonal Antibodies, and Their Influence on Binding to FXII Zhang, Ying Vontz, Alexander J. Kallenberger, Ethan M. Xu, Xin Ploscariu, Nicoleta T. Ramyar, Kasra X. Garcia, Brandon L. Ghebrehiwet, Berhane Geisbrecht, Brian V. Front Immunol Immunology The protein gC1qR/C1qBP/HABP-1 plays an essential role in mitochondrial biogenesis, but becomes localized at the cellular surface in numerous pathophysiological states. When this occurs on endothelial cells, surface-exposed gC1qR activates the classical pathway of complement. It also promotes assembly of a multi-protein complex comprised of coagulation factor XII (FXII), pre-kallikrein (PK), and high-molecular weight kininogen (HMWK) that activates the contact system and the kinin-generating system. Since surface-exposed gC1qR triggers intravascular inflammatory pathways, there is interest in identifying molecules that block gC1qR function. Here we further that objective by reporting the outcome of a structure/function investigation of gC1qR, its interactions with FXII, and the impact of a panel of monoclonal anti-gC1qR antibodies on FXII binding to gC1qR. Although deletion mutants have been used extensively to assess gC1qR function, none of these proteins have been characterized structurally. To that end, we determined a 2.2 Å resolution crystal structure of a gC1qR mutant lacking both of its acidic loops, but which retained nanomolar-affinity binding to FXII and FXIIa. This structure revealed that the trimeric gC1qR assembly was maintained despite loss of roughly thirty residues. Characterization of a novel panel of anti-gC1qR monoclonal antibodies identified several with biochemical properties distinct from previously described antibodies, as well as one which bound to the first acidic loop of gC1qR. Intriguingly, we found that each of these antibodies could partly inhibit binding of FXII and FXIIa to gC1qR. Based on these results and previously published studies, we offer new perspectives for developing gC1qR inhibitors. Frontiers Media S.A. 2022-07-05 /pmc/articles/PMC9294231/ /pubmed/35865516 http://dx.doi.org/10.3389/fimmu.2022.887742 Text en Copyright © 2022 Zhang, Vontz, Kallenberger, Xu, Ploscariu, Ramyar, Garcia, Ghebrehiwet and Geisbrecht https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Zhang, Ying
Vontz, Alexander J.
Kallenberger, Ethan M.
Xu, Xin
Ploscariu, Nicoleta T.
Ramyar, Kasra X.
Garcia, Brandon L.
Ghebrehiwet, Berhane
Geisbrecht, Brian V.
gC1qR/C1qBP/HABP-1: Structural Analysis of the Trimeric Core Region, Interactions With a Novel Panel of Monoclonal Antibodies, and Their Influence on Binding to FXII
title gC1qR/C1qBP/HABP-1: Structural Analysis of the Trimeric Core Region, Interactions With a Novel Panel of Monoclonal Antibodies, and Their Influence on Binding to FXII
title_full gC1qR/C1qBP/HABP-1: Structural Analysis of the Trimeric Core Region, Interactions With a Novel Panel of Monoclonal Antibodies, and Their Influence on Binding to FXII
title_fullStr gC1qR/C1qBP/HABP-1: Structural Analysis of the Trimeric Core Region, Interactions With a Novel Panel of Monoclonal Antibodies, and Their Influence on Binding to FXII
title_full_unstemmed gC1qR/C1qBP/HABP-1: Structural Analysis of the Trimeric Core Region, Interactions With a Novel Panel of Monoclonal Antibodies, and Their Influence on Binding to FXII
title_short gC1qR/C1qBP/HABP-1: Structural Analysis of the Trimeric Core Region, Interactions With a Novel Panel of Monoclonal Antibodies, and Their Influence on Binding to FXII
title_sort gc1qr/c1qbp/habp-1: structural analysis of the trimeric core region, interactions with a novel panel of monoclonal antibodies, and their influence on binding to fxii
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9294231/
https://www.ncbi.nlm.nih.gov/pubmed/35865516
http://dx.doi.org/10.3389/fimmu.2022.887742
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