4hkc
14-3-3-zeta in complex with S1011 phosphorylated integrin alpha-4 peptide
Structural highlights
Function1433Z_HUMAN 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.[1] [2] [3] [4] [5] Publication Abstract from PubMedIntegrins are a family of heterodimeric (alpha+beta) adhesion receptors that play key roles in many cellular processes. Integrins are unusual in that their functions can be modulated from both outside and inside the cell. Inside-out signaling is mediated by binding adaptor proteins to the flexible cytoplasmic tails of the alpha- and beta-integrin subunits. Talin is one well-known intracellular activator, but various other adaptors bind to integrin tails, including 14-3-3-zeta, a member of the 14-3-3 family of dimeric proteins that have a preference for binding phosphorylated sequence motifs. Phosphorylation of a threonine in the beta2 integrin tail has been shown to modulate beta2/14-3-3-zeta interactions, and recently, the alpha4 integrin tail was reported to bind to 14-3-3-zeta and associate with paxillin in a ternary complex that is regulated by serine phosphorylation. Here, we use a range of biophysical techniques to characterize interactions between 14-3-3-zeta and the cytoplasmic tails of alpha4, beta1, beta2 and beta3 integrins. The X-ray structure of the 14-3-3-zeta/alpha4 complex indicates a canonical binding mode for the alpha4 phospho-peptide, but unexpected features are also observed: residues outside the consensus 14-3-3-zeta binding motif are shown to be essential for an efficient interaction; in contrast, a short beta2 phospho-peptide is sufficient for high-affinity binding to 14-3-3-zeta. In addition, we report novel 14-3-3-zeta/integrin tail interactions that are independent of phosphorylation. Of the integrin tails studied, the strongest interaction with 14-3-3-zeta is observed for the beta1A variant. In summary, new insights about 14-3-3-zeta/integrin tail interactions that have implications for the role of these molecular associations in cells are described. Characterization of 14-3-3-zeta Interactions with Integrin Tails.,Bonet R, Vakonakis I, Campbell ID J Mol Biol. 2013 Jun 11. pii: S0022-2836(13)00354-9. doi:, 10.1016/j.jmb.2013.05.024. PMID:23763993[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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