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Low-affinity integrin states have faster ligand-binding kinetics than the high-affinity state

Integrin conformational ensembles contain two low-affinity states, bent-closed and extended-closed, and an active, high-affinity, extended-open state. It is widely thought that integrins must be activated before they bind ligand; however, one model holds that activation follows ligand binding. As li...

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Detalles Bibliográficos
Autores principales: Li, Jing, Yan, Jiabin, Springer, Timothy A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8730728/
https://www.ncbi.nlm.nih.gov/pubmed/34854380
http://dx.doi.org/10.7554/eLife.73359
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author Li, Jing
Yan, Jiabin
Springer, Timothy A
author_facet Li, Jing
Yan, Jiabin
Springer, Timothy A
author_sort Li, Jing
collection PubMed
description Integrin conformational ensembles contain two low-affinity states, bent-closed and extended-closed, and an active, high-affinity, extended-open state. It is widely thought that integrins must be activated before they bind ligand; however, one model holds that activation follows ligand binding. As ligand-binding kinetics are not only rate limiting for cell adhesion but also have important implications for the mechanism of activation, we measure them here for integrins α4β1 and α5β1 and show that the low-affinity states bind substantially faster than the high-affinity state. On- and off-rates are similar for integrins on cell surfaces and as ectodomain fragments. Although the extended-open conformation’s on-rate is ~20-fold slower, its off-rate is ~25,000-fold slower, resulting in a large affinity increase. The tighter ligand-binding pocket in the open state may slow its on-rate. Low-affinity integrin states not only bind ligand more rapidly, but are also more populous on the cell surface than high-affinity states. Thus, our results suggest that integrin binding to ligand may precede, rather than follow, activation by ‘inside-out signaling.’
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spelling pubmed-87307282022-01-06 Low-affinity integrin states have faster ligand-binding kinetics than the high-affinity state Li, Jing Yan, Jiabin Springer, Timothy A eLife Biochemistry and Chemical Biology Integrin conformational ensembles contain two low-affinity states, bent-closed and extended-closed, and an active, high-affinity, extended-open state. It is widely thought that integrins must be activated before they bind ligand; however, one model holds that activation follows ligand binding. As ligand-binding kinetics are not only rate limiting for cell adhesion but also have important implications for the mechanism of activation, we measure them here for integrins α4β1 and α5β1 and show that the low-affinity states bind substantially faster than the high-affinity state. On- and off-rates are similar for integrins on cell surfaces and as ectodomain fragments. Although the extended-open conformation’s on-rate is ~20-fold slower, its off-rate is ~25,000-fold slower, resulting in a large affinity increase. The tighter ligand-binding pocket in the open state may slow its on-rate. Low-affinity integrin states not only bind ligand more rapidly, but are also more populous on the cell surface than high-affinity states. Thus, our results suggest that integrin binding to ligand may precede, rather than follow, activation by ‘inside-out signaling.’ eLife Sciences Publications, Ltd 2021-12-02 /pmc/articles/PMC8730728/ /pubmed/34854380 http://dx.doi.org/10.7554/eLife.73359 Text en © 2021, Li et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Li, Jing
Yan, Jiabin
Springer, Timothy A
Low-affinity integrin states have faster ligand-binding kinetics than the high-affinity state
title Low-affinity integrin states have faster ligand-binding kinetics than the high-affinity state
title_full Low-affinity integrin states have faster ligand-binding kinetics than the high-affinity state
title_fullStr Low-affinity integrin states have faster ligand-binding kinetics than the high-affinity state
title_full_unstemmed Low-affinity integrin states have faster ligand-binding kinetics than the high-affinity state
title_short Low-affinity integrin states have faster ligand-binding kinetics than the high-affinity state
title_sort low-affinity integrin states have faster ligand-binding kinetics than the high-affinity state
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8730728/
https://www.ncbi.nlm.nih.gov/pubmed/34854380
http://dx.doi.org/10.7554/eLife.73359
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