{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T18:15:11Z","timestamp":1791051311549,"version":"4.1.0"},"reference-count":70,"publisher":"The Royal Society","issue":"7","license":[{"start":{"date-parts":[[2012,7,1]],"date-time":"2012-07-01T00:00:00Z","timestamp":1341100800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/royalsociety.org\/journals\/ethics-policies\/data-sharing-mining\/"}],"content-domain":{"domain":["royalsocietypublishing.org"],"crossmark-restriction":true},"short-container-title":["Open Biol."],"published-print":{"date-parts":[[2012,7]]},"abstract":"<jats:p>14-3-3 proteins regulate cellular responses to stimuli by docking onto pairs of phosphorylated residues on target proteins. The present study shows that the human 14-3-3-binding phosphoproteome is highly enriched in 2R-ohnologues, which are proteins in families of two to four members that were generated by two rounds of whole genome duplication at the origin of the vertebrates. We identify 2R-ohnologue families whose members share a \u2018lynchpin\u2019, defined as a 14-3-3-binding phosphosite that is conserved across members of a given family, and aligns with a Ser\/Thr residue in pro-orthologues from the invertebrate chordates. For example, the human receptor expression enhancing protein (REEP) 1\u20134 family has the commonest type of lynchpin motif in current datasets, with a phosphorylatable serine in the \u20132 position relative to the 14-3-3-binding phosphosite. In contrast, the second 14-3-3-binding sites of REEPs 1\u20134 differ and are phosphorylated by different kinases, and hence the REEPs display different affinities for 14-3-3 dimers. We suggest a conceptual model for intracellular regulation involving protein families whose evolution into signal multiplexing systems was facilitated by 14-3-3 dimer binding to lynchpins, which gave freedom for other regulatory sites to evolve. While increased signalling complexity was needed for vertebrate life, these systems also generate vulnerability to genetic disorders.<\/jats:p>","DOI":"10.1098\/rsob.120103","type":"journal-article","created":{"date-parts":[[2012,7,26]],"date-time":"2012-07-26T02:15:23Z","timestamp":1343268923000},"page":"120103","update-policy":"https:\/\/doi.org\/10.1098\/crossmark-policy","source":"Crossref","is-referenced-by-count":55,"title":["Evolution of signal multiplexing by 14-3-3-binding 2R-ohnologue protein families in the vertebrates"],"prefix":"10.1098","volume":"2","author":[{"given":"Michele","family":"Tinti","sequence":"first","affiliation":[{"name":"MRC Protein Phosphorylation Unit, College of Life Sciences, James Black Centre, University of Dundee, Dow Street, Dundee DD1 5EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Johnson","sequence":"additional","affiliation":[{"name":"MRC Protein Phosphorylation Unit, College of Life Sciences, James Black Centre, University of Dundee, Dow Street, Dundee DD1 5EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Toth","sequence":"additional","affiliation":[{"name":"MRC Protein Phosphorylation Unit, College of Life Sciences, James Black Centre, University of Dundee, Dow Street, Dundee DD1 5EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David E. 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