Review14-3-3 proteins: A historic overview
Introduction
Members of the 14-3-3 protein family form a group of highly conserved 30 kDa acidic proteins expressed in a wide range of organisms and tissues. The five major mammalian brain 14-3-3 isoforms are named α–η after their respective elution positions on HPLC [1], [2]. α and δ are the phosphoforms of β and ζ, respectively [3]. Two other isoforms τ (also known as θ) and σ are expressed in T cells and epithelial cells, respectively, although the former is also widely expressed in other tissues including brain. 14-3-3 is now established as a family of dimeric proteins that can modulate interaction between proteins (including oncogene products of polyoma middle T, Raf-1, AKT and Bcr-Abl). They are involved in cell signalling, regulation of cell cycle progression, intracellular trafficking/targeting, cytoskeletal structure and transcription. In many cases, the interacting proteins show a distinct preference for a particular isoform(s) of 14-3-3. A specific repertoire of dimer formation may influence which of the 14-3-3 interacting proteins could be brought together. The regulation of interaction usually involves phosphorylation of the interacting protein and in some cases the phosphorylation of 14-3-3 isoforms themselves may modulate interaction.
Section snippets
Discovery and name
The name 14-3-3 was given to an abundant mammalian brain protein family due to its particular elution and migration pattern on two-dimensional DEAE-cellulose chromatography and starch gel electrophoresis [4]. The 14-3-3 proteins elute in the 14th fraction of bovine brain homogenate from the authors’ “homemade” DEAE cellulose column and fractions 3.3 in the latter step. Members of the family have been given many other names when they have been rediscovered by other researchers due to their
Occurrence of 14-3-3 family and sequence conservation
The 14-3-3 family is highly conserved over a wide range of mammalian species, where the individual isoforms, β, ɛ, η, γ, τ (also called θ), ζ and σ are largely identical, but contain a few regions of diversity. Homologues of 14-3-3 proteins have also been found in a broad range of eukaryotic organisms and are probably ubiquitous (reviewed in [30], [31]). In almost every known organism, multiple (at least two) isoforms of 14-3-3 have been observed [32] and at least 12 (probably 15) isoforms are
Structures of 14-3-3 dimers and their interactions
The first 14-3-3 structures to be determined were the τ and ζ isoforms [39], [40]. These studies showed that they are highly helical, dimeric proteins. Each monomer is composed of nine antiparallel α-helices, organised into an N-terminal and a C-terminal domain. The dimer creates a large negatively charged channel. Those regions of the 14-3-3 protein, which are invariant throughout all the isoforms are mainly found lining the interior of this channel, while the variable residues are located on
The 14-3-3 binding motif
Muslin et al. [50] demonstrated that a novel phosphoserine containing motif initially identified in Raf kinase was important for interaction, and showed that target protein phosphorylation is important for 14-3-3 binding. The motif was further refined into two sub-types: RSXpSXP (mode I) and RXY/FXpSXP (mode II) [51] where pS is phosphoserine. There are also six known interacting proteins with a novel carboxy terminal, -pS/pT X1-2-CO2 H “mode III” motif (where X is not Pro) [52]. Novel roles
Phosphorylation of 14-3-3 isoforms
The regulation of interaction with 14-3-3 through phosphorylation of the target protein is now well established and many reviews have been published on the subject [[64], [65] and this issue]. Recently, it is also becoming clear that the phosphorylation of 14-3-3 isoforms on specific residues (summarised in Fig. 1) has an important regulatory role—in this case by preventing interaction. A number of examples of the regulation of large signalling complexes by are shown in Fig. 2A and B. This
Non-phosphorylated and novel 14-3-3 binding motifs
Some well-characterised interacting proteins such as Raf kinase have been shown to have additional binding site(s) for 14-3-3 on their cysteine-rich regions. Bcr also binds via a serine-rich region.
Along with several other 14-3-3 binding proteins, Exoenzyme S (ExoS), the ADP-ribosyltransferase toxin secreted by the bacterium Pseudomonas aeruginosa, interacts with 14-3-3 in a phosphorylation-independent mechanism [85]. The DALDL sequence in ExoS (residues 424–428 at the C-terminus) that is
Summary/conclusions
Many names have been ascribed to 14-3-3 proteins, depending on the discoverers of a particular novel role (Table 1). However, the name “14-3-3” is well established now and the name is functionally neutral. This may well be an advantage given that members of the family are now known to have so many diverse roles, across the whole eukaryote phyla (and since 14-3-3 also interacts with other biomolecules including DNA) [15]. The accumulated literature on 14-3-3 over the past few years shows how
Acknowledgement
The work in the author's laboratory was supported by the Medical Research Council, EU and Wellcome Trust.
References (125)
- et al.
14-3-3 alpha and delta are the phosphorylated forms of Raf-activating 14-3-3 beta and zeta In vivo stoichiometric phosphorylation in brain at a Ser-Pro-Glu-Lys MOTIF
J Biol Chem
(1995) - et al.
Brain 14-3-3 protein is an activator protein that activates tryptophan 5-monooxygenase and tyrosine 3-monooxygenase in the presence of Ca2+ calmodulin-dependent protein kinase II
FEBS Lett
(1987) - et al.
Activation-modulated association of 14-3-3 proteins with Cbl in T cells
J Biol Chem
(1996) - et al.
14-3-3 zeta protein binds to the carboxyl half of mouse wee1 kinase
Biochem Biophys Res Commun
(1997) - et al.
14-3-3 proteins interact with specific MEK kinases
J Biol Chem
(1998) - et al.
Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization
Curr Biol
(2004) - et al.
Comprehensive proteomic analysis of interphase and mitotic 14-3-3-binding proteins
J Biol Chem
(2004) - et al.
Targeted proteomic analysis of 14-3-3 sigma, a p53 effector commonly silenced in cancer
Mol Cell Proteomics
(2005) - et al.
Neurofibrillary tangles of Alzheimer's disease brains contain 14-3-3 proteins
Neurosci Lett
(1996) - et al.
Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1
Cell
(2003)