Editors' ChoiceProtein Domains

New Tricks for the Old PH Domain

Science Signaling  02 Dec 2008:
Vol. 1, Issue 48, pp. ec417
DOI: 10.1126/scisignal.148ec417

The pleckstrin homology (PH) domain binds to phosphoinositide products formed by activity of PI3K (phosphatidylinositol 3-kinase) and thus has been described as a modular domain that allows controlled membrane localization of various signaling molecules. Swanson et al. now show that the PH domain in Skap-hom (Src-kinase–associated phosphoprotein of 55 kD homolog), an adaptor protein that functions in linking integrins to cytoskeletal rearrangement, has a critical role in controlling targeting of Skap-hom to membrane ruffles, but by a different mechanism. Their structural studies of Skap-hom showed that the protein forms dimers through a dimerization domain that interacts with the PH domain in a way that alters the structure of the phosphoinositide-binding portion of the PH domain and prevents phosphoinositide binding. In mouse bone marrow macrophages, mutant Skap-hom proteins lacking the PH domain still bound to actin-rich ruffles, but treatment of the cells with a pharmacological inhibitor of PI3K caused dissociation of Skap-hom from the cytoskeleton. The authors reasoned that the PH domain might mediate an autoinhibitory domain interaction within Skap-hom that prevents association of Skap-hom with ruffles and that binding of 3′-phosphoinositides would relieve this inhibition. Indeed, mutations that disrupted both phosphoinositide binding by the PH domain and the intramolecular interaction with the dimerization domain yielded a protein whose association of Skap-hom to ruffles was similar to that of the wild-type protein. Thus, the authors propose that signaling through activity of PI3 kinases and phosphatases is likely to regulate association of Skap-hom with membrane ruffles, although it remains to be determined whether this PH domain–mediated molecular switch controls actual generation of the ruffles, targeting of Skap-hom to the ruffles, or both.

K. D. Swanson, Y. Tang, D. F. Ceccarelli, F. Poy, J. P. Sliwa, B. G. Neel, M. J. Eck, The Skap-hom dimerization and PH domains comprise a 3′-phosphoinositide-gated molecular switch. Mol. Cell 32, 564–575 (2008). [PubMed]