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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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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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.’ |
format | Online Article Text |
id | pubmed-8730728 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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