PH domains: diverse sequences with a common fold recruit signaling molecules to the cell surface.

With the identification of two distinct classes of high affinity, physiologically relevant, ligands for PH domains, it appears reasonable to assume that additional specific high affinity ligands for other PH domains will be identified in the future. It is not clear, however, whether each of the 90 proposed PH domains will have its own specific ligand. Possible candidates for specific PH domain ligands include various inositol polyphosphates, phosphorylated membrane components, as well as specific protein sequences containing phosphorylated tyrosine, serine, threonine, or histidine residues. It appears unlikely that the low affinity interactions of phosphoinositides described for several PH domains are physiologically relevant. It is difficult to imagine why such a large and diverse family of PH domains (with just 10-15% sequence identity) would exist in order to bind with a similar low affinity to PtdInsP2-containing membranes. Rather, we suggest that these interactions represent limited binding to noncognate ligands - the physiologically relevant ligands have yet to be identified. It is likely that many, if not all, PH domains have their own high affinity, cell membrane-associated, ligands and operate according to the paradigms described for the PH domains of PLCδ1 and Shc (Figure 2Figure 2A and Figure 2Figure 2B). The structural homology between PH domains might reflect a particularly stable protein scaffold of β sheets that can present variable ligand-binding loops in a manner analogous to that seen in the immunoglobulin superfamily.