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Regulation of multiple dimeric states of E-cadherin by adhesion activating antibodies revealed through Cryo-EM and X-ray crystallography

E-cadherin adhesion is regulated at the cell surface, a process that can be replicated by activating antibodies. We use cryo-electron microscopy (EM) and X-ray crystallography to examine functional states of the cadherin adhesive dimer. This dimer is mediated by N-terminal beta strand-swapping invol...

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Autores principales: Maker, Allison, Bolejack, Madison, Schecterson, Leslayann, Hammerson, Brad, Abendroth, Jan, Edwards, Thomas E, Staker, Bart, Myler, Peter J, Gumbiner, Barry M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9491697/
https://www.ncbi.nlm.nih.gov/pubmed/36157596
http://dx.doi.org/10.1093/pnasnexus/pgac163
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author Maker, Allison
Bolejack, Madison
Schecterson, Leslayann
Hammerson, Brad
Abendroth, Jan
Edwards, Thomas E
Staker, Bart
Myler, Peter J
Gumbiner, Barry M
author_facet Maker, Allison
Bolejack, Madison
Schecterson, Leslayann
Hammerson, Brad
Abendroth, Jan
Edwards, Thomas E
Staker, Bart
Myler, Peter J
Gumbiner, Barry M
author_sort Maker, Allison
collection PubMed
description E-cadherin adhesion is regulated at the cell surface, a process that can be replicated by activating antibodies. We use cryo-electron microscopy (EM) and X-ray crystallography to examine functional states of the cadherin adhesive dimer. This dimer is mediated by N-terminal beta strand-swapping involving Trp2, and forms via a different transient X-dimer intermediate. X-dimers are observed in cryo-EM along with monomers and strand-swap dimers, indicating that X-dimers form stable interactions. A novel EC4-mediated dimer was also observed. Activating Fab binding caused no gross structural changes in E-cadherin monomers, but can facilitate strand swapping. Moreover, activating Fab binding is incompatible with the formation of the X-dimer. Both cryo-EM and X-ray crystallography reveal a distinctive twisted strand-swap dimer conformation caused by an outward shift in the N-terminal beta strand that may represent a strengthened state. Thus, regulation of adhesion involves changes in cadherin dimer configurations.
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spelling pubmed-94916972022-09-22 Regulation of multiple dimeric states of E-cadherin by adhesion activating antibodies revealed through Cryo-EM and X-ray crystallography Maker, Allison Bolejack, Madison Schecterson, Leslayann Hammerson, Brad Abendroth, Jan Edwards, Thomas E Staker, Bart Myler, Peter J Gumbiner, Barry M PNAS Nexus Biological, Health, and Medical Sciences E-cadherin adhesion is regulated at the cell surface, a process that can be replicated by activating antibodies. We use cryo-electron microscopy (EM) and X-ray crystallography to examine functional states of the cadherin adhesive dimer. This dimer is mediated by N-terminal beta strand-swapping involving Trp2, and forms via a different transient X-dimer intermediate. X-dimers are observed in cryo-EM along with monomers and strand-swap dimers, indicating that X-dimers form stable interactions. A novel EC4-mediated dimer was also observed. Activating Fab binding caused no gross structural changes in E-cadherin monomers, but can facilitate strand swapping. Moreover, activating Fab binding is incompatible with the formation of the X-dimer. Both cryo-EM and X-ray crystallography reveal a distinctive twisted strand-swap dimer conformation caused by an outward shift in the N-terminal beta strand that may represent a strengthened state. Thus, regulation of adhesion involves changes in cadherin dimer configurations. Oxford University Press 2022-08-19 /pmc/articles/PMC9491697/ /pubmed/36157596 http://dx.doi.org/10.1093/pnasnexus/pgac163 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of National Academy of Sciences. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Biological, Health, and Medical Sciences
Maker, Allison
Bolejack, Madison
Schecterson, Leslayann
Hammerson, Brad
Abendroth, Jan
Edwards, Thomas E
Staker, Bart
Myler, Peter J
Gumbiner, Barry M
Regulation of multiple dimeric states of E-cadherin by adhesion activating antibodies revealed through Cryo-EM and X-ray crystallography
title Regulation of multiple dimeric states of E-cadherin by adhesion activating antibodies revealed through Cryo-EM and X-ray crystallography
title_full Regulation of multiple dimeric states of E-cadherin by adhesion activating antibodies revealed through Cryo-EM and X-ray crystallography
title_fullStr Regulation of multiple dimeric states of E-cadherin by adhesion activating antibodies revealed through Cryo-EM and X-ray crystallography
title_full_unstemmed Regulation of multiple dimeric states of E-cadherin by adhesion activating antibodies revealed through Cryo-EM and X-ray crystallography
title_short Regulation of multiple dimeric states of E-cadherin by adhesion activating antibodies revealed through Cryo-EM and X-ray crystallography
title_sort regulation of multiple dimeric states of e-cadherin by adhesion activating antibodies revealed through cryo-em and x-ray crystallography
topic Biological, Health, and Medical Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9491697/
https://www.ncbi.nlm.nih.gov/pubmed/36157596
http://dx.doi.org/10.1093/pnasnexus/pgac163
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