14-3-3s are phosphoprotein-binding proteins that mediate many cellular responses to extracellular stimuli. Via this web resource, the emerging mammalian 14-3-3-interactome can be examined in several ways:
1 - Search for published human 14-3-3-binding phosphoproteins and phosphosites
Search for published data on proteins and phosphosites that dock onto 14-3-3s. The data are from studies that each examined one or a few phosphoproteins that bind to 14-3-3s, and also high-throughput 14-3-3-affinity capture and mass spectrometry-based studies. The latter datasets will likely include phosphoproteins that dock directly onto 14-3-3s, proteins that bind to 14-3-3s indirectly within larger protein complexes, and also nonspecific contaminants. One goal of this web resource is to facilitate the identification of those phosphoproteins that are direct targets of 14-3-3s.
2 - Map of the human kinome in terms of 2R-ohnologue proteins that bind to 14-3-3s
Many well-defined 14-3-3-binding human phosphoproteins belong to families of 2R-ohnologues, which were generated by two rounds of whole genome duplication (2R-WGD) at the evolutionary origins of the vertebrate animals. We aim to map the overlap between 2R-ohnologue protein families and the 14-3-3-interactome. Towards this goal, this resource includes a draft map of the 14-3-3-binding proteins and 2R-ohnologue protein families within the human kinome. While certain protein kinases create 14-3-3-binding phosphosites, many protein kinases are also themselves 14-3-3-binding phosphoproteins and/or 2R-ohnologues. Here, the protein kinases within each 2R-ohnologue family can be aligned, and searched for experimentally-defined 14-3-3-binding phosphosites, and also for candidate 'lynchpin' phosphosites (see 3). Note that by definition, a 2R-ohnologue family does not contain more than four protein-coding genes, unless there have been further duplications after the 2R-WGD. However, sometimes there is insufficient data to sort larger families of paralogues into their respective 2R-ohnologue subsets, and these are left unresolved as families of five or more as a temporary measure (Tinti et al (2012) PMID: 22870394 ).
3 - Identification of candidate 'lynchpins' and other 14-3-3-binding phosphosites
A 'lynchpin' is defined as a 14-3-3-binding phosphosite that is conserved across members of a given 2R-ohnologue family, including the single pro-orthologue in the invertebrate chordate animals, amphioxus and Ciona, which are proxy for the pre-2R-WGD ancestor. Candidate 'lynchpins' can be identified in this resource, and may help guide experimental investigations. 14-3-3 proteins are dimers and many target proteins contain two 14-3-3-binding phosphosites.