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.

Was this article helpful?

0 0
Diabetes Sustenance

Diabetes Sustenance

Get All The Support And Guidance You Need To Be A Success At Dealing With Diabetes The Healthy Way. This Book Is One Of The Most Valuable Resources In The World When It Comes To Learning How Nutritional Supplements Can Control Sugar Levels.

Get My Free Ebook

Post a comment