The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Functional site class:
14-3-3 ligand
Functional site description:
14-3-3 proteins interact with specific phosphoserine or phosphothreonine containing motifs.
ELMs with same func. site: LIG_14-3-3_1  LIG_14-3-3_2  LIG_14-3-3_3 
ELM Description:
The longer mode 2 interacting phospho-motif for 14-3-3 proteins with key conservation RxxxS#p where # is a conserved hydrophobic position and p is a semiconserved Pro. Pro is excluded -1 and +1 of the pSer due to tight backbone interactions. Pro is usually depicted as required at +2 but (unlike mode 1) it is neither strongly conserved nor making tight contact to 14-3-3. Instead the +1 residue is always a conserved hydrophobic with an extensive packing face. Other residue preferences in the x positions are likely to affect binding affinity and some combinations may be disfavoured. The typical kinases phosphorylating mode 2 peptides are likely to have a positive charge preference preceding the phosphorylated residue.
Pattern: R..[^P]([ST])[IVLM].
Pattern Probability: 0.0015569
Present in taxons: Arabidopsis thaliana Bos taurus Dictyostelium discoideum Eukaryota Gallus gallus Homo sapiens Mus musculus Rattus norvegicus Saccharomyces cerevisiae Schizosaccharomyces pombe Xenopus laevis
Interaction Domain:
14-3-3 (PF00244) 14-3-3 protein (Stochiometry: 1 : 1)
o See 7 Instances for LIG_14-3-3_2
o Abstract
The 14-3-3 proteins constitute a family of conserved proteins present in all eukaryotic organisms so far investigated, including seven isotypes in human cells. They occur as homo- or heterodimers. They are involved in important cellular processes such as signal transduction, cell-cycle control, apoptosis, stress response and malignant transformation. More than one hundred different binding partners for these proteins have been reported so far. 14-3-3 proteins were the first signaling molecules to be identified as discrete phosphoserine/threonine binding modules, although cases of phosphorylation-independent interaction have been reported. While many details of the biochemical and cellular functions of 14-3-3 proteins remain to be elucidated, they are known to act as adaptor molecules to mediate protein-protein interactions, the subcellular localisation and to regulate enzyme activities. Though 14-3-3 proteins perform different functions for different ligands, general mechanisms of 14-3-3 action include changes in activity of bound ligands, altered association of bound ligands with other cellular components, and changes in intracellular localization of 14-3-3-bound cargo.

The classical mode 1 and mode 2 binding motifs are compatible with phosphorylation by e.g. PKA, PKB and other kinases with a positive charge preference and it is likely that these are the typical kinases phosphorylating 14-3-3-binding sites. On the other hand the C-terminal peptide from plant H+ ATPases - QSYpTV* - lacks a positive charge and will be phosphorylated by another class of kinase. This does raise the question of how often non-canonical 14-3-3 binding peptides will lack a positive residue preceding the phosphorylation site.

14-3-3 proteins are targeted by certain fungal toxins and bacterial virulence factors. Fusicoccin toxin stabilises an H+ ATPase phosphopeptide interaction with 14-3-3 (Wurtele,2003). The non-phosphorylated Pseudomonas exoS peptide LLDALDL binds in the reverse orientation to the phosphorylated peptides and it is possible that there are cellular equivalents of this binding mode (Ottmann,2007). It is thought that all non-phosphorylated peptides will bind in the reverse orientation.
o 21 selected references:

o 13 GO-Terms:

o 7 Instances for LIG_14-3-3_2
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
P08965 mei2
523 529 TGSLGMRRSLTVGANASCSN TP 4 Schizosaccharomyces pombe 972h-
P32418 SLC8A1
388 394 HAADQARKAVSMHEVNTEVT TP 2 Homo sapiens (Human)
Q04206 RELA
41 47 RYKCEGRSAGSIPGERSTDT TP 2 Homo sapiens (Human)
Q14432 PDE3A
424 430 KLAIPKRLRRSLPPGLLRRV TP 2 Homo sapiens (Human)
A2ALK8 Ptpn3
355 361 VWNPVMRRSLSVERLETKSL TP 2 Mus musculus (House mouse)
P98177 FOXO4
193 199 SGKAPRRRAASMDSSSKLLR TP 2 Homo sapiens (Human)
Q63572 Tesk1
435 441 QPETPVRRCRSLPSSPELPR TP 2 Rattus norvegicus (Norway rat)
Please cite: ELM 2016-data update and new functionality of the eukaryotic linear motif resource. (PMID:26615199)

ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement