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Heterotropic roles of divalent cations in the establishment of allostery and affinity maturation of integrin αXβ2
Allosteric activation and silencing of leukocyte β2-integrins transpire through cation-dependent structural changes, which mediate integrin biosynthesis and recycling, and are essential to designing leukocyte-specific drugs. Stepwise addition of Mg(2+) reveals two mutually coupled events for the αXβ...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9440770/ https://www.ncbi.nlm.nih.gov/pubmed/36001965 http://dx.doi.org/10.1016/j.celrep.2022.111254 |
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author | Manandhar, Pragya Mazhar, Zahra Abousaway, Omar Aboagye, Collins Moussa, Zeinab Lim, Daniel Yu, Tannon Byrnes, James Briggs, James M. Sen, Mehmet |
author_facet | Manandhar, Pragya Mazhar, Zahra Abousaway, Omar Aboagye, Collins Moussa, Zeinab Lim, Daniel Yu, Tannon Byrnes, James Briggs, James M. Sen, Mehmet |
author_sort | Manandhar, Pragya |
collection | PubMed |
description | Allosteric activation and silencing of leukocyte β2-integrins transpire through cation-dependent structural changes, which mediate integrin biosynthesis and recycling, and are essential to designing leukocyte-specific drugs. Stepwise addition of Mg(2+) reveals two mutually coupled events for the αXβ2 ligand-binding domain—the αX I-domain—corresponding to allostery establishment and affinity maturation. Electrostatic alterations in the Mg(2+)-binding site establish long-range couplings, leading to both pH− and Mg(2+)-occupancy-dependent biphasic stability change in the αX I-domain fold. The ligand-binding sensorgrams show composite affinity events for the αX I-domain accounting for the multiplicity of the αX I-domain conformational states existing in the solution. On cell surfaces, increasing Mg(2+) concentration enhanced adhesiveness of αXβ2. This work highlights how intrinsically flexible pH− and cation-sensitive architecture endows a unique dynamic continuum to the αI-domain structure on the intact integrin, thereby revealing the importance of allostery establishment and affinity maturation in both extracellular and intracellular integrin events. |
format | Online Article Text |
id | pubmed-9440770 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
record_format | MEDLINE/PubMed |
spelling | pubmed-94407702022-09-03 Heterotropic roles of divalent cations in the establishment of allostery and affinity maturation of integrin αXβ2 Manandhar, Pragya Mazhar, Zahra Abousaway, Omar Aboagye, Collins Moussa, Zeinab Lim, Daniel Yu, Tannon Byrnes, James Briggs, James M. Sen, Mehmet Cell Rep Article Allosteric activation and silencing of leukocyte β2-integrins transpire through cation-dependent structural changes, which mediate integrin biosynthesis and recycling, and are essential to designing leukocyte-specific drugs. Stepwise addition of Mg(2+) reveals two mutually coupled events for the αXβ2 ligand-binding domain—the αX I-domain—corresponding to allostery establishment and affinity maturation. Electrostatic alterations in the Mg(2+)-binding site establish long-range couplings, leading to both pH− and Mg(2+)-occupancy-dependent biphasic stability change in the αX I-domain fold. The ligand-binding sensorgrams show composite affinity events for the αX I-domain accounting for the multiplicity of the αX I-domain conformational states existing in the solution. On cell surfaces, increasing Mg(2+) concentration enhanced adhesiveness of αXβ2. This work highlights how intrinsically flexible pH− and cation-sensitive architecture endows a unique dynamic continuum to the αI-domain structure on the intact integrin, thereby revealing the importance of allostery establishment and affinity maturation in both extracellular and intracellular integrin events. 2022-08-23 /pmc/articles/PMC9440770/ /pubmed/36001965 http://dx.doi.org/10.1016/j.celrep.2022.111254 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ). |
spellingShingle | Article Manandhar, Pragya Mazhar, Zahra Abousaway, Omar Aboagye, Collins Moussa, Zeinab Lim, Daniel Yu, Tannon Byrnes, James Briggs, James M. Sen, Mehmet Heterotropic roles of divalent cations in the establishment of allostery and affinity maturation of integrin αXβ2 |
title | Heterotropic roles of divalent cations in the establishment of allostery and affinity maturation of integrin αXβ2 |
title_full | Heterotropic roles of divalent cations in the establishment of allostery and affinity maturation of integrin αXβ2 |
title_fullStr | Heterotropic roles of divalent cations in the establishment of allostery and affinity maturation of integrin αXβ2 |
title_full_unstemmed | Heterotropic roles of divalent cations in the establishment of allostery and affinity maturation of integrin αXβ2 |
title_short | Heterotropic roles of divalent cations in the establishment of allostery and affinity maturation of integrin αXβ2 |
title_sort | heterotropic roles of divalent cations in the establishment of allostery and affinity maturation of integrin αxβ2 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9440770/ https://www.ncbi.nlm.nih.gov/pubmed/36001965 http://dx.doi.org/10.1016/j.celrep.2022.111254 |
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