ArticleProceedings of the National Academy of Sciences of the United States of America2005
Disrupting integrin transmembrane domain heterodimerization increases ligand binding affinity, not valency or clustering.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers.
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Who cites it
69 citing papers in PubMed, 154 citations in OpenAlex.
- Membrane-Based Assembly and Interactions in Immune Receptors.Chemical reviews · 2026Review
- FCHo2, not talin, enables inside-out activation of integrin ɑvβ5 in curved adhesions.Nature communications · 2026Article
- FCHo2, instead of talin, enables inside-out activation of integrin ɑvβ5 in curved adhesions.bioRxiv : the preprint server for biology · 2025Article
- Allosteric Disulfide Bridges in Integrins: The Molecular Switches of Redox Regulation of Integrin-Mediated Cell Functions.Antioxidants (Basel, Switzerland) · 2025Review
- In silico framework about prediction of collagen-derived matrikine generation and its ligand function binding to integrin [Formula: see text] for malignancy of colon cancer.In silico pharmacology · 2025Article
- Coordinating Cytoskeleton and Molecular Traffic in T Cell Migration, Activation, and Effector Functions.Frontiers in cell and developmental biology · 2020Review
- Intramembrane ionic protein-lipid interaction regulates integrin structure and function.PLoS biology · 2018Article
- Nanodiscs: A Controlled Bilayer Surface for the Study of Membrane Proteins.Annual review of biophysics · 2018Article
- On the contributing role of the transmembrane domain for subunit-specific sensitivity of integrin activation.Scientific reports · 2018Article
- Conformational equilibria and intrinsic affinities define integrin activation.The EMBO journal · 2017Article
- Article
- Conformational equilibrium of talin is regulated by anionic lipids.Biochimica et biophysica acta · 2016Article
- Directly Activating the Integrin αIIbβ3 Initiates Outside-In Signaling by Causing αIIbβ3 Clustering.The Journal of biological chemistry · 2016Article
- Three-Dimensional Structures of Full-Length, Membrane-Embedded Human α(IIb)β(3) Integrin Complexes.Biophysical journal · 2016Article
- Action and Traction: Cytoskeletal Control of Receptor Triggering at the Immunological Synapse.Frontiers in immunology · 2016Review
- The dual structural roles of the membrane distal region of the α-integrin cytoplasmic tail during integrin inside-out activation.Journal of cell science · 2015Article
- CW-EPR studies revealed different motional properties and oligomeric states of the integrin β1a transmembrane domain in detergent micelles or liposomes.Scientific reports · 2015Article
- The influenza virus neuraminidase protein transmembrane and head domains have coevolved.Journal of virology · 2015Article
- Leukocyte arrest: Biomechanics and molecular mechanisms of β2 integrin activation.Biorheology · 2015Review
- Integrin αIIbβ3 transmembrane domain separation mediates bi-directional signaling across the plasma membrane.PloS one · 2015Article
9 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Residues important in the interaction between the 23-residue transmembrane (TM) domains of the integrin alpha(IIb)- and beta(3)-subunits were identified by mutating each non-Leu residue to Leu. Leu substitutions of alpha(IIb) at G972, G976, and T981, and of beta(3) at I693 and G708, increased ligand binding. Substitutions with other amino acids at alpha(IIb)G972 and beta(3)G708 could also increase ligand binding. The results are consistent with and extend the helical interface between the integrin alpha- and beta-subunit TM domains previously defined by cysteine scanning and disulfide bond formation. We differentiated between affinity- and valency-based modes of activation by TM domain mutations. The mutant alpha(IIb) W967C forms disulfide-linked alpha(IIb)-subunits within an (alpha(IIb)beta(3))(2) tetramer. This tetramer behaved as an ideal model for the valency mode of regulation, because it exhibited significantly increased binding to multivalent but not monovalent ligands and basally retained the bent conformation. By contrast, the activating Leu mutants showed increased binding to the monovalent, ligand-mimetic PAC-1 Fab and increased exposure of ligand-induced binding site (LIBS) epitopes, suggesting that they partially adopt an extended conformation. Furthermore, the previously described beta(3)G708N mutation in Chinese hamster ovary cells enhanced ligand binding affinity, not valency, and did not alter cell-surface clustering as defined by confocal microscopy. Our studies provide evidence that disrupting the integrin heterodimeric TM helix-helix interface activates ligand binding mainly by increasing the monomeric affinity for ligand, but not the receptor valency, i.e., clustering.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.