NDLI: Disrupting integrin transmembrane domain heterodimerization increases ligand binding affinity, not valency or clustering

Content Provider	PubMed Central
Author	Luo, Bing-hao Carman, Christopher V. Takagi, Junichi Springer, Timothy A.
Copyright Year	2005
Abstract	Residues important in the interaction between the 23-residue transmembrane (TM) domains of the integrin αIIb- and β3-subunits were identified by mutating each non-Leu residue to Leu. Leu substitutions of αIIb at G972, G976, and T981, and of β3 at I693 and G708, increased ligand binding. Substitutions with other amino acids at αIIbG972 and β3G708 could also increase ligand binding. The results are consistent with and extend the helical interface between the integrin α- and β-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 αIIb W967C forms disulfide-linked αIIb-subunits within an (αIIbβ3)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 β3G708N 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.
Related Links	http://dx.doi.org/10.1073/pnas.0409440102
Ending Page	3684
Page Count	6
Starting Page	3679
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	10
Volume Number	102
Language	English
Publisher	National Academy of Sciences
Publisher Date	2005-03-08
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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