2v7d
14-3-3 protein zeta in complex with Thr758 phosphorylated integrin beta2 peptide
Structural highlights
Function1433Z_BOVIN Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Activates the ADP-ribosyltransferase (exoS) activity of bacterial origin.[1] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedLeukocyte integrins of the beta2 family are essential for immune cell-cell adhesion. In activated cells, beta2 integrins are phosphorylated on the cytoplasmic Thr758, leading to 14-3-3 protein recruitment to the beta2 integrin. The mutation of this phosphorylation site impairs cell adhesion, actin reorganization and cell spreading. Thr758 is contained in a Thr-triplet of beta2 that also mediates binding to filamin. Here, we investigated the binding of filamin, talin and 14-3-3 proteins to phosphorylated and unphosphorylated beta2 integrins by biochemical methods and X-ray crystallography. 14-3-3 proteins bound only to the phosphorylated integrin cytoplasmic peptide, with a high affinity (Kd 261 nM), whereas filamin bound only the unphosphorylated integrin cytoplasmic peptide (Kd 0.5 mM). Phosphorylation did not regulate talin binding to beta2 directly, but 14-3-3 was able to out-compete talin for the binding to phosphorylated beta2-integrin. X-ray crystallographic data clearly explained how phosphorylation eliminated filamin binding and induced 14-3-3 protein binding. Filamin knockdown in T cells led to an increase in stimulated cell adhesion to ICAM-1-coated surfaces. Our results suggest that the phosphorylation of beta2 integrins on Thr758 acts as a molecular switch to inhibit filamin binding and allow 14-3-3 protein binding to the integrin cytoplasmic domain, thereby modulating T cell adhesion. Integrin {beta}2 phosphorylation on THR758 acts as a molecular switch to regulate 14-3-3 and filamin binding.,Takala H, Nurminen E, Nurmi SM, Aatonen M, Strandin T, Takatalo M, Kiema T, Gahmberg CG, Ylanne J, Fagerholm SC Blood. 2008 Jun 12;. PMID:18550856[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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