2rlo
Split PH domain of PI3-kinase enhancer
Structural highlights
FunctionAGAP2_HUMAN GTPase-activating protein (GAP) for ARF1 and ARF5, which also shows strong GTPase activity. Isoform 1 participates in the prevention of neuronal apoptosis by enhancing PI3 kinase activity. It aids the coupling of metabotropic glutamate receptor 1 (GRM1) to cytoplasmic PI3 kinase by interacting with Homer scaffolding proteins, and also seems to mediate anti-apoptotic effects of NGF by activating nuclear PI3 kinase. Isoform 2 does not stimulate PI3 kinase but may protect cells from apoptosis by stimulating Akt. It also regulates the adapter protein 1 (AP-1)-dependent trafficking of proteins in the endosomal system. It seems to be oncogenic. It is overexpressed in cancer cells, prevents apoptosis and promotes cancer cell invasion.[1] [2] [3] [4] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedCytoplasm-nucleus shuttling of phosphoinositol 3-kinase enhancer (PIKE) is known to correlate directly with its cellular functions. However, the molecular mechanism governing this shuttling is not known. In this work, we demonstrate that PIKE is a new member of split pleckstrin homology (PH) domain-containing proteins. The structure solved in this work reveals that the PIKE PH domain is split into halves by a positively charged nuclear localization sequence. The PIKE PH domain binds to the head groups of di- and triphosphoinositides with similar affinities. Lipid membrane binding of the PIKE PH domain is further enhanced by the positively charged nuclear localization sequence, which is juxtaposed to the phosphoinositide head group-binding pocket of the domain. We demonstrate that the cytoplasmic-nuclear shuttling of PIKE is dynamically regulated by the balancing actions of the lipid-binding property of both the split PH domain and the nuclear targeting function of its nuclear localization sequence. Split pleckstrin homology domain-mediated cytoplasmic-nuclear localization of PI3-kinase enhancer GTPase.,Yan J, Wen W, Chan LN, Zhang M J Mol Biol. 2008 Apr 25;378(2):425-35. Epub 2008 Mar 4. PMID:18371979[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||
