The first phosphoserine/threonine-binding molecules that were identified were members of a family of dimeric proteins called 14-3-3 that were first identified as abundant polypeptides of unknown function in brain [2]; they were later identified as activators of tryptophan and tyrosine hydroxylase [3,4] and as inhibitors or activators of PKCs [5]. Mammalian cells contain 7 distinct 14-3-3 gene products (denoted p, y, e, n, o, t, and Z), while plants and fungi contain between 2 and 15. Several of the mammalian 14-3-3 isotypes are subject to phosphorylation, although the role that phosphorylation plays in 14-3-3 function remains speculative.

The initial observation that 14-3-3-binding might be regulated by ligand phosphorylation emerged from studies of tryptophan hydroxylase [6] and Raf, the upstream activator of the classical mitogen-activated protein (MAP) kinase pathway [7]. Detailed investigation of the 14-3-3 binding sites on Raf [8], together with oriented peptide library screening on all mammalian 14-3-3s [9] led to the identification of two optimal pSer/threonine-containing motifs, RSXpSXP and RXXXpSXP, that are recognized by all 14-3-3 isotypes (pS denotes both pSer and pThr, and X denotes any amino acid, although there are preferences for particular amino acids in different X positions). Over 100 14-3-3 binding proteins have been identified to date, and many, though not all, use phosphorylated sequences that closely match the optimal 14-3-3 consensus motifs for binding.

Comprehensive referenced and tabulated lists of 14-3-3-binding proteins are available within detailed reviews [10,11]. In many cases, the mechanistic role of 14-3-3-bind-ing is not known, though for a smaller subset of ligands detailed studies are beginning to uncover general mechanisms through which 14-3-3 may regulate their function. For some ligands, 14-3-3 proteins can directly regulate their

Handbook of Cell Signaling, Volume 1

Figure 1 14-3-3/phosphopeptide interactions. Dimerization of two 14-3-3 monomers, each of which is composed of nine a-helices, forms a cleft within which phosphoserine-containing ligands bind (shown in ball-and-stick representation). A single, multiply phosphorylated protein ligand may bind simultaneously to both available sites. Alternatively, two singly phosphorylated proteins can bind, one to each monomer, allowing 14-3-3 to act as a molecular scaffold for the assembly of diverse signaling complexes [9,24]. Reprinted from Yaffe and Smerdon [75], with permission.

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