1ywt

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spinqualitylabelsall models 1ywt, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of the human sigma isoform of 14-3-3 in complex with a mode-1 phosphopeptide

Overview

The 14-3-3 family of proteins includes seven isotypes in mammalian cells, that play numerous diverse roles in intracellular signaling. Most 14-3-3, proteins form homodimers and mixed heterodimers between different, isotypes, with overlapping roles in ligand binding. In contrast, one, mammalian isoform, 14-3-3sigma, expressed primarily in epithelial cells, appears to play a unique role in the cellular response to DNA damage and, in human oncogenesis. The biological and structural basis for these, 14-3-3sigma-specific functions is unknown. We demonstrate that endogenous, 14-3-3sigma preferentially forms homodimers in cells. We have solved the, x-ray crystal structure of 14-3-3sigma bound to an optimal phosphopeptide, ligand at 2.4 angstroms resolution. The structure reveals the presence of, stabilizing ring-ring and salt bridge interactions unique to the, 14-3-3sigma homodimer structure and potentially destabilizing, electrostatic interactions between subunits in 14-3-3sigma-containing, heterodimers, rationalizing preferential homodimerization of 14-3-3sigma, in vivo. The interaction of the phosphopeptide with 14-3-3 reveals a, conserved mechanism for phospho-dependent ligand binding, implying that, the phosphopeptide binding cleft is not the critical determinant of the, unique biological properties of 14-3-3sigma. Instead, the structure, suggests a second ligand binding site involved in 14-3-3sigma-specific, ligand discrimination. We have confirmed this by site-directed mutagenesis, of three sigma-specific residues that uniquely define this site. Mutation, of these residues to the alternative sequence that is absolutely conserved, in all other 14-3-3 isotypes confers upon 14-3-3sigma the ability to bind, to Cdc25C, a ligand that is known to bind to other 14-3-3 proteins but not, to sigma.

About this Structure

1YWT is a Single protein structure of sequence from Homo sapiens with CA as ligand. Full crystallographic information is available from OCA.

Reference

A structural basis for 14-3-3sigma functional specificity., Wilker EW, Grant RA, Artim SC, Yaffe MB, J Biol Chem. 2005 May 13;280(19):18891-8. Epub 2005 Feb 24. PMID:15731107

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