Novel Gbeta Mimic Kelch Proteins Gpb1 and Gpb2 Connect G-Protein Signaling to Ras Via Yeast Neurofibromin Homologs Ira 1 and Ira 2: A Model for Human NF1
Annual rept. 1 Mar 2004-28 Feb 2005
DUKE UNIV MEDICAL CENTER DURHAM NC
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The Neurofibromatosis type 1 NF1 gene encodes a large tumor suppressor protein, neurofibromin, which is a Ras GTPase-activating protein RasGAP activity. Although the NF1 gene was identified over a decade ago, the biological roles of neurofibromin in cellular processes remain unclear. Therefore it is crucial for therapy and developing new drugs for NF1 patients to elucidate how the RasGAP activity of neurofibromin is controlled. To achieve this goal, it is also important to identify regulatory elements for neurofibromin. We are investigating the molecular mechanisms by which the Ras GAP activity of the yeast neurofibromin homologs Ira12 is regulated as a model to understand human NFl. We have found that the kelch GBeta subunit mimics Gpb12 interact with Ira12 and control the Ras GAP activity of Ira12. Here, we found that the Gpb12 proteins are localized to the cell membrane in a Gpa2 dependent manner and function at the cell membrane. Gpb12 bind to the C-terminus of Ira12 and stabilize the Ira12 proteins. Moreover we also identified a Gpb12 binding domain near the C-terminus of Ira12 GBD that is significantly conserved in neurofibromin homologs, including a human counterpart. Therefore, similar regulatory mechanisms might be conserved in evolution.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research