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Cryo-EM structure of the αvβ8 integrin reveals a mechanism for stabilizing integrin extension

Integrins are conformationally flexible cell surface receptors that survey the extracellular environment for their cognate ligands. Interactions with ligands are thought to be linked to global structural rearrangements involving transitions between bent, extended-closed and -open forms. Thus far, st...

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Autores principales: Cormier, Anthony, Campbell, Melody G., Ito, Saburo, Wu, Shenping, Lou, Jianlong, Marks, James, Baron, Jody, Nishimura, Stephen L., Cheng, Yifan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214843/
https://www.ncbi.nlm.nih.gov/pubmed/30061598
http://dx.doi.org/10.1038/s41594-018-0093-x
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author Cormier, Anthony
Campbell, Melody G.
Ito, Saburo
Wu, Shenping
Lou, Jianlong
Marks, James
Baron, Jody
Nishimura, Stephen L.
Cheng, Yifan
author_facet Cormier, Anthony
Campbell, Melody G.
Ito, Saburo
Wu, Shenping
Lou, Jianlong
Marks, James
Baron, Jody
Nishimura, Stephen L.
Cheng, Yifan
author_sort Cormier, Anthony
collection PubMed
description Integrins are conformationally flexible cell surface receptors that survey the extracellular environment for their cognate ligands. Interactions with ligands are thought to be linked to global structural rearrangements involving transitions between bent, extended-closed and -open forms. Thus far, structural details are lacking for integrins in the extended conformation due to extensive flexibility between the headpiece and legs within this conformation. Here we present single-particle electron cryo-microscopy structures of human αvβ8 integrin in the extended-closed conformation, which has been considered to be a low-affinity intermediate. Our structures show the headpiece rotating about a flexible αv-knee, suggesting a ligand surveillance mechanism for integrins in their extended-closed form. Our model predicts that the extended conformation is mainly stabilized by an interface formed between flexible loops in the upper and lower domains of the αv-leg. Confirming these findings with the αvβ3 integrin suggests that our model of stabilizing the extended-closed conformation is generalizable to other integrins.
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spelling pubmed-62148432019-01-30 Cryo-EM structure of the αvβ8 integrin reveals a mechanism for stabilizing integrin extension Cormier, Anthony Campbell, Melody G. Ito, Saburo Wu, Shenping Lou, Jianlong Marks, James Baron, Jody Nishimura, Stephen L. Cheng, Yifan Nat Struct Mol Biol Article Integrins are conformationally flexible cell surface receptors that survey the extracellular environment for their cognate ligands. Interactions with ligands are thought to be linked to global structural rearrangements involving transitions between bent, extended-closed and -open forms. Thus far, structural details are lacking for integrins in the extended conformation due to extensive flexibility between the headpiece and legs within this conformation. Here we present single-particle electron cryo-microscopy structures of human αvβ8 integrin in the extended-closed conformation, which has been considered to be a low-affinity intermediate. Our structures show the headpiece rotating about a flexible αv-knee, suggesting a ligand surveillance mechanism for integrins in their extended-closed form. Our model predicts that the extended conformation is mainly stabilized by an interface formed between flexible loops in the upper and lower domains of the αv-leg. Confirming these findings with the αvβ3 integrin suggests that our model of stabilizing the extended-closed conformation is generalizable to other integrins. 2018-07-30 2018-08 /pmc/articles/PMC6214843/ /pubmed/30061598 http://dx.doi.org/10.1038/s41594-018-0093-x Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Cormier, Anthony
Campbell, Melody G.
Ito, Saburo
Wu, Shenping
Lou, Jianlong
Marks, James
Baron, Jody
Nishimura, Stephen L.
Cheng, Yifan
Cryo-EM structure of the αvβ8 integrin reveals a mechanism for stabilizing integrin extension
title Cryo-EM structure of the αvβ8 integrin reveals a mechanism for stabilizing integrin extension
title_full Cryo-EM structure of the αvβ8 integrin reveals a mechanism for stabilizing integrin extension
title_fullStr Cryo-EM structure of the αvβ8 integrin reveals a mechanism for stabilizing integrin extension
title_full_unstemmed Cryo-EM structure of the αvβ8 integrin reveals a mechanism for stabilizing integrin extension
title_short Cryo-EM structure of the αvβ8 integrin reveals a mechanism for stabilizing integrin extension
title_sort cryo-em structure of the αvβ8 integrin reveals a mechanism for stabilizing integrin extension
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214843/
https://www.ncbi.nlm.nih.gov/pubmed/30061598
http://dx.doi.org/10.1038/s41594-018-0093-x
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