Heterotropic roles of divalent cations in the establishment of allostery and affinity maturation of integrin αXβ2
Abstract
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 Mg2+ 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 Mg2+-binding site establish long-range couplings, leading to both pH- and Mg2+-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 Mg2+ 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.
- Authors:
-
- University of Houston, TX (United States); Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source II (NSLS-II)
- University of Houston, TX (United States)
- Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source II (NSLS-II)
- Publication Date:
- Research Org.:
- Brookhaven National Lab. (BNL), Upton, NY (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER)
- OSTI Identifier:
- 1889175
- Report Number(s):
- BNL-223437-2022-JAAM
Journal ID: ISSN 2211-1247
- Grant/Contract Number:
- SC0012704; R03 AI139651; P30GM133893; KP1605010; S10 OD012331
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Cell Reports
- Additional Journal Information:
- Journal Volume: 40; Journal Issue: 8; Journal ID: ISSN 2211-1247
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 36 MATERIALS SCIENCE; CD11c; CD18; integrin; allostery; αX I-domain; affinity maturation
Citation Formats
Manandhar, Pragya, Mazhar, Zahra, Abousaway, Omar, Aboagye, Collins, Moussa, Zeinab, Lim, Daniel, Yu, Tannon, Byrnes, James, Briggs, James M., and Sen, Mehmet. Heterotropic roles of divalent cations in the establishment of allostery and affinity maturation of integrin αXβ2. United States: N. p., 2022.
Web. doi:10.1016/j.celrep.2022.111254.
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. United States. https://doi.org/10.1016/j.celrep.2022.111254
Manandhar, Pragya, Mazhar, Zahra, Abousaway, Omar, Aboagye, Collins, Moussa, Zeinab, Lim, Daniel, Yu, Tannon, Byrnes, James, Briggs, James M., and Sen, Mehmet. Tue .
"Heterotropic roles of divalent cations in the establishment of allostery and affinity maturation of integrin αXβ2". United States. https://doi.org/10.1016/j.celrep.2022.111254. https://www.osti.gov/servlets/purl/1889175.
@article{osti_1889175,
title = {Heterotropic roles of divalent cations in the establishment of allostery and affinity maturation of integrin αXβ2},
author = {Manandhar, Pragya and Mazhar, Zahra and Abousaway, Omar and Aboagye, Collins and Moussa, Zeinab and Lim, Daniel and Yu, Tannon and Byrnes, James and Briggs, James M. and Sen, Mehmet},
abstractNote = {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 Mg2+ 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 Mg2+-binding site establish long-range couplings, leading to both pH- and Mg2+-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 Mg2+ 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.},
doi = {10.1016/j.celrep.2022.111254},
journal = {Cell Reports},
number = 8,
volume = 40,
place = {United States},
year = {Tue Aug 23 00:00:00 EDT 2022},
month = {Tue Aug 23 00:00:00 EDT 2022}
}
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