Journal
CELL REPORTS
Volume 40, Issue 8, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2022.111254
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Funding
- NIH [NIAID R03 AI139651]
- National University Research Fund
- Center for BioMolecular Structure (CBMS)
- National Institutes of Health (NIH)
- National Institute of General Medical Sciences (NIGMS) [P30GM133893]
- Department of Energy Office of Biological and Environmental Research [KP1605010]
- NIH [S10 OD012331]
- US Department of Energy, Office of Science, Office of Basic Energy Sciences Program [DE-SC0012704]
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Allosteric activation and silencing of leukocyte beta 2-integrins occur through cation-dependent structural changes, which are essential for designing leukocyte-specific drugs. The study reveals that the alpha X I-domain exhibits composite affinity events in response to pH and Mg2+ conditions, and increasing Mg2+ concentration enhances the adhesiveness of alpha X beta 2 on cell surfaces.
Allosteric activation and silencing of leukocyte beta 2-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 alpha X beta 2 ligand-binding domain-the alpha X 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+-occu-pancy-dependent biphasic stability change in the alpha X I-domain fold. The ligand-binding sensorgrams show composite affinity events for the alpha X I-domain accounting for the multiplicity of the aX I-domain conformational states existing in the solution. On cell surfaces, increasing Mg2+ concentration enhanced adhesiveness of alpha X beta 2. This work highlights how intrinsically flexible pH-and cation-sensitive architecture endows a unique dynamic continuum to the aIdomain structure on the intact integrin, thereby revealing the importance of allostery establishment and affinity maturation in both extracellular and intracellular integrin events.
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