The regulation of membrane to cytosol partitioning of signalling proteins by phosphoinositides and their soluble headgroups

C. P. Downes, A. Gray, A. Fairservice, S. T. Safrany, I. H. Batty, I. Fleming

    Research output: Contribution to journalArticlepeer-review

    23 Citations (Scopus)

    Abstract

    Inositol phospholipids [PIs (phosphoinositides)] represent a group of membrane-tethered signalling molecules which differ with respect to the number and distribution of monoester phosphate groups around the inositol ring. They function by binding to proteins which possess one of several domains that bind a particular PI species, often with high affinity and specificity. PH (pleckstrin homology) domains for example possess ligand-binding pockets that are often lined with positively charged residues and which bind PIs with varying degrees of specificity. Several PH domains bind not only PIs, but also their cognate headgroups, many of which occur naturally in cells as relatively abundant cytosolic inositol phosphates. The subcellular distributions of proteins possessing such PH domains are therefore determined by the relative levels of competing membrane-bound and soluble ligands. A classic example of the latter is the PH domain of phospholipase Cδ1, which binds both phosphatidylinositol 4,5-bisphosphate and inositol 1,4,5-trisphosphate. We have shown that the N-terminal PH domain of the Rho family guanine nucleotide-exchange factor, Tiam 1, binds PI ligands promiscuously allowing multiple modes of regulation. We also recently analysed the ligand-binding specificity of the PH domain of PI-dependent kinase 1 and found that it could bind abundant inositol polyphosphates such as inositol hexakisphosphate. This could explain the dual distribution of this key signalling component, which needs to access substrates at both the plasma membrane and in the cytosol.

    Original languageEnglish
    Pages (from-to)1303-1307
    Number of pages5
    JournalBiochemical Society Transactions
    Volume33
    Issue number6
    DOIs
    Publication statusPublished - Dec 2005

    Keywords

    • Cytosol partitioning
    • phosphoinositide (PI)
    • Phosphoinositide-dependent kinase 1 (PDK1)
    • Pleckstrin homology domain (PH domain)
    • Signalling protein
    • Tiam1

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