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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Peng, Hong-juan Mahankali, Madhu Dinauer, Mary C. Henkels, Karen M. Gomez-cambronero, Julian |
| Description | Author Affiliation: Mahankali M ( Department of Biochemistry and Molecular Biology, Wright State University School of Medicine, Dayton, OH 45435, USA.); |
| Abstract | We have discovered that the enzyme phospholipase D2 (PLD2) binds directly to the small GTPase Rac2, resulting in PLD2 functioning as a guanine nucleotide exchange factor (GEF), because it switches Rac2 from the GDP-bound to the GTP-bound states. This effect is large enough to be meaningful (â ¼72% decrease for GDP dissociation and 300% increase for GTP association, both with PLD2), it has a half-time of â ¼7 min, is enhanced with increasing PLD2 concentrations, and compares favorably with other known GEFs, such as Vav-1. The PLD2-Rac2 protein-protein interaction is sufficient for the GEF function, because it can be demonstrated in vitro with just recombinant proteins without lipid substrates, and a catalytically inactive lipase (PLD2-K758R) has GEF activity. Apart from this function, exogenous phosphatidic acid by itself (300 pM) increases GTP binding and enhances PLD2-K758R-mediated GTP binding (by â ¼34%) but not GDP dissociation. Regarding the PLD2-Rac2 protein-protein association, it involves, for PLD2, residues 263-266 within a Cdc42/Rac interactive binding region in the PH domain, as well as the PX domain, and it involves, for Rac2, residue N17 within its Switch-1 region. PLD2's GEF function is demonstrated in living cells, because silencing PLD2 results in reduced Rac2 activity, whereas PLD2-initiated Rac2 activation enhances cell adhesion, chemotaxis, and phagocytosis. There are several known GEFs, but we report that this GEF is harbored in a phospholipase. The benefit to the cell is that PLD2 brings spatially separated molecules together in a membrane environment, ready for fast intracellular signaling and cell function. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 49 |
| Volume Number | 108 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2011-12-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Guanine Nucleotide Exchange Factors Metabolism Phospholipase D Rac GTP-Binding Proteins Animals Binding Sites Genetics COS Cells Cell Line Cells, Cultured Cercopithecus Aethiops Guanosine Diphosphate Guanosine Triphosphate Immunoblotting Microscopy, Fluorescence Mutation Phosphatidic Acids Pharmacology Protein Binding Drug Effects RNA Interference Recombinant Proteins Spodoptera Research Support, N.I.H., Extramural Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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