Accession Number : ADA486604


Title :   Identification of Novel Molecular Targets for Pleckstrin Homology (PH) Domains Found in Oncogenes Implicated in Breast Cancer


Descriptive Note : Annual summary rept. 23 Feb 2004-22 Feb 2008


Corporate Author : PENNSYLVANIA UNIV PHILADELPHIA


Personal Author(s) : Keleti, David


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a486604.pdf


Report Date : Mar 2008


Pagination or Media Count : 22


Abstract : Plecktrin Homology (PH) domains are commonly thought of as membrane-targeting modules involved in signaling pathways that bind phosphoinositides (PPIns) with high affinity and specificity. In a recent study of S. cerevisiae, however, the vast majority demonstrated little affinity or specificity for PPIns (Yu et al, 2004). I show comparable results for selected human PH domains, with one that is high affinity and PPIns-specific, while the remainder are low to moderate affinity and promiscuous for PPIns. I outline two instances where protein-protein and protein-phosphoinositide interactions may account for specific membrane targeting observed in vivo. First, SH3BP-2 PH was identified as highly specific for the membrane lipid PtdIns(3,4)P2, and targets the host protein to the membrane. Second, FAPP1- and OSBP PH domains possess comparable affinities for Golgi- and plama membrane (PM)-enriched PPIns in vitro, although they both localize to the Golgi (not the PM) in vivo, possibly by directly interacting with the Golgi GTPase Arf1. In vitro binding studies suggest that delocalized electrostatic attraction between the basic protein and acidic phospholipids play a prominent role in these interactions. Additionally, I have solved the crystal structure of a related member of this PH domain family in complex with PPIns.


Descriptors :   *ONCOGENIC VIRUSES , *PHOSPHOLIPIDS , *BREAST CANCER , IN VITRO ANALYSIS , IN VIVO ANALYSIS , ACIDS , PROTEINS , CRYSTAL STRUCTURE , MEMBRANES(BIOLOGY) , TARGETING


Subject Categories : Biochemistry
      Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE