Tyrosine Phosphorylation as a Conformational Switch: A CASE STUDY OF INTEGRIN β

Reversible protein phosphorylation is vital for many fundamental cellular processes. The actual impact of adding and removing phosphate group(s) is 3-fold: changes in the local/global geometry, alterations in the electrostatic potential and, as the result of both, modified protein-target interaction...

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Bibliographic Details
Published in:The Journal of biological chemistry 2011-09, Vol.286 (47), p.40943-40953
Main Authors: Deshmukh, Lalit, Meller, Nahum, Alder, Nathan, Byzova, Tatiana, Vinogradova, Olga
Format: Article
Language:English
Subjects:
Protein Structure and Folding
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Summary:Reversible protein phosphorylation is vital for many fundamental cellular processes. The actual impact of adding and removing phosphate group(s) is 3-fold: changes in the local/global geometry, alterations in the electrostatic potential and, as the result of both, modified protein-target interactions. Here we present a comprehensive structural investigation of the effects of phosphorylation on the conformational as well as functional states of a crucial cell surface receptor, α IIb β 3 integrin. We have analyzed phosphorylated (Tyr 747 and Tyr 759 ) β 3 integrin cytoplasmic tail (CT) primarily by NMR, and our data demonstrate that under both aqueous and membrane-mimetic conditions, phosphorylation causes substantial conformational rearrangements. These changes originate from novel ionic interactions and revised phospholipid binding. Under aqueous conditions, the critical Tyr 747 phosphorylation prevents β 3 CT from binding to its heterodimer partner α IIb CT, thus likely maintaining an activated state of the receptor. This conclusion was tested in vivo and confirmed by integrin-dependent endothelial cells adhesion assay. Under membrane-mimetic conditions, phosphorylation results in a modified membrane embedding characterized by significant changes in the secondary structure pattern and the overall fold of β 3 CT. Collectively these data provide unique molecular insights into multiple regulatory roles of phosphorylation.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M111.231951