Evolution of signal multiplexing by 14-3-3-binding 2R-ohnologue protein families in the vertebrates

Michele Tinti, Catherine Johnson, Rachel Toth, David E. K. Ferrier, Carol MacKintosh (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    27 Citations (Scopus)

    Abstract

    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 ‘lynchpin’, 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) 1–4 family has the commonest type of lynchpin motif in current datasets, with a phosphorylatable serine in the –2 position relative to the 14-3-3-binding phosphosite. In contrast, the second 14-3-3-binding sites of REEPs 1–4 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.
    Original languageEnglish
    Article number120103
    JournalOpen Biology
    Volume2
    Issue number7
    DOIs
    Publication statusPublished - 2012

    Fingerprint

    Multiplexing
    Vertebrates
    vertebrates
    Dimers
    Nonvertebrate Chordata
    Proteins
    proteins
    14-3-3 Proteins
    Inborn Genetic Diseases
    Chordata
    genetic disorders
    serine
    Serine
    binding sites
    phosphotransferases (kinases)
    Phosphotransferases
    protein synthesis
    Genes
    invertebrates
    Binding Sites

    Cite this

    @article{c8b0861c7d5d4ff686bc12cbbc0dd786,
    title = "Evolution of signal multiplexing by 14-3-3-binding 2R-ohnologue protein families in the vertebrates",
    abstract = "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 ‘lynchpin’, 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) 1–4 family has the commonest type of lynchpin motif in current datasets, with a phosphorylatable serine in the –2 position relative to the 14-3-3-binding phosphosite. In contrast, the second 14-3-3-binding sites of REEPs 1–4 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.",
    author = "Michele Tinti and Catherine Johnson and Rachel Toth and Ferrier, {David E. K.} and Carol MacKintosh",
    year = "2012",
    doi = "10.1098/rsob.120103",
    language = "English",
    volume = "2",
    journal = "Open Biology",
    issn = "2046-2441",
    publisher = "The Royal Society",
    number = "7",

    }

    Evolution of signal multiplexing by 14-3-3-binding 2R-ohnologue protein families in the vertebrates. / Tinti, Michele; Johnson, Catherine; Toth, Rachel; Ferrier, David E. K.; MacKintosh, Carol (Lead / Corresponding author).

    In: Open Biology, Vol. 2, No. 7, 120103, 2012.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Evolution of signal multiplexing by 14-3-3-binding 2R-ohnologue protein families in the vertebrates

    AU - Tinti, Michele

    AU - Johnson, Catherine

    AU - Toth, Rachel

    AU - Ferrier, David E. K.

    AU - MacKintosh, Carol

    PY - 2012

    Y1 - 2012

    N2 - 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 ‘lynchpin’, 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) 1–4 family has the commonest type of lynchpin motif in current datasets, with a phosphorylatable serine in the –2 position relative to the 14-3-3-binding phosphosite. In contrast, the second 14-3-3-binding sites of REEPs 1–4 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.

    AB - 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 ‘lynchpin’, 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) 1–4 family has the commonest type of lynchpin motif in current datasets, with a phosphorylatable serine in the –2 position relative to the 14-3-3-binding phosphosite. In contrast, the second 14-3-3-binding sites of REEPs 1–4 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.

    UR - http://www.scopus.com/inward/record.url?scp=84873901523&partnerID=8YFLogxK

    U2 - 10.1098/rsob.120103

    DO - 10.1098/rsob.120103

    M3 - Article

    VL - 2

    JO - Open Biology

    JF - Open Biology

    SN - 2046-2441

    IS - 7

    M1 - 120103

    ER -