Nanobody inhibitors of Plexin-B1 identify allostery in plexin-semaphorin interactions and signaling.

Animals Mice Receptors, Cell Surface / metabolism Semaphorins / metabolism Signal Transduction Single-Domain Antibodies Cell Adhesion Molecules / metabolism
cancer multiple sclerosis phage display semaphorin single-domain antibody (sdAb, nanobody, VHH)

Journal

The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R

Informations de publication

Date de publication:
06 2023
Historique:
received: 28 11 2022
revised: 29 03 2023
accepted: 18 04 2023
medline: 28 6 2023
pubmed: 24 4 2023
entrez: 23 04 2023
Statut: ppublish

Résumé

Plexin-B1 is a receptor for the cell surface semaphorin, Sema4D. This signaling system has been implicated in a variety of human diseases, including cancer, multiple sclerosis and osteoporosis. While inhibitors of the Plexin-B1:Sema4D interaction have been previously reported, understanding their mechanism has been hindered by an incomplete structural view of Plexin-B1. In this study, we have raised and characterized a pair of nanobodies that are specific for mouse Plexin-B1 and which inhibit the binding of Sema4D to mouse Plexin-B1 and its biological activity. Structural studies of these nanobodies reveal that they inhibit the binding of Sema4D in an allosteric manner, binding to epitopes not previously reported. In addition, we report the first unbound structure of human Plexin-B1, which reveals that Plexin-B1 undergoes a conformational change on Sema4D binding. These changes mirror those seen upon binding of allosteric peptide modulators, which suggests a new model for understanding Plexin-B1 signaling and provides a potential innovative route for therapeutic modulation of Plexin-B1.

Identifiants

DOI: 10.1016/j.jbc.2023.104740 PMID: 37088134 PMC: PMC10206189
pubmed: 37088134
pii: S0021-9258(23)01768-4
doi: 10.1016/j.jbc.2023.104740
pmc: PMC10206189
pii:
doi:

Substances chimiques

plexin 0
Receptors, Cell Surface 0
Semaphorins 0
Single-Domain Antibodies 0
Cell Adhesion Molecules 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

104740

Informations de copyright

Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Conflict of interest The authors declare no conflicts of interest with the contents of this article.

Auteurs

Richard Cowan (R)

Department of Molecular and Cell Biology, Leicester Institute of Structural and Chemical Biology, University of Leicester, Leicester, UK.

Martina Trokter (M)

LifeArc, Centre for Therapeutics Discovery, Stevenage, UK.

Arkadiusz Oleksy (A)

LifeArc, Centre for Therapeutics Discovery, Stevenage, UK.

Marina Fedorova (M)

LifeArc, Centre for Therapeutics Discovery, Stevenage, UK.

Kovilen Sawmynaden (K)

LifeArc, Centre for Therapeutics Discovery, Stevenage, UK.

Thomas Worzfeld (T)

Institute of Pharmacology, University of Marburg, Marburg, Germany; Department of Pharmacology, Max-Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.

Stefan Offermanns (S)

Department of Pharmacology, Max-Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.

David Matthews (D)

LifeArc, Centre for Therapeutics Discovery, Stevenage, UK.

Mark D Carr (MD)

Department of Molecular and Cell Biology, Leicester Institute of Structural and Chemical Biology, University of Leicester, Leicester, UK.

Gareth Hall (G)

Department of Molecular and Cell Biology, Leicester Institute of Structural and Chemical Biology, University of Leicester, Leicester, UK. Electronic address: gh126@leicester.ac.uk.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Nanobody inhibitors of Plexin-B1 identify...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Nanobody inhibitors of Plexin-B1 identify...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Nanobody inhibitors of Plexin-B1 identify...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Sémaphorines › Nanobody inhibitors of Plexin-B1 identify...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Nanobody inhibitors of Plexin-B1 identify...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Fragments d'immunoglobuline › Fragments Fab d'immunoglobuline › Anticorps à domaine unique › Nanobody inhibitors of Plexin-B1 identify...
questionsmedicales.fr › Facteurs biologiques › Antigènes › Antigènes de surface › Molécules d'adhérence cellulaire › Nanobody inhibitors of Plexin-B1 identify...