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          Institute: MPI für molekulare Physiologie     Collection: Sonstige wissenschaftliche Organisationseinheiten     Display Documents



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ID: 34951.0, MPI für molekulare Physiologie / Sonstige wissenschaftliche Organisationseinheiten
Structural fingerprints of the Ras-GTPase activating proteins neurofibromin and p120GAP
Authors:Ahmadian, Mohammad Reza; Kiel, Christina; Stege, Patricia; Scheffzek, Klaus
Language:English
Research Context:GTPase activating proteins
Date of Publication (YYYY-MM-DD):2003-06-13
Title of Journal:Journal of Molecular Biology
Journal Abbrev.:J. Mol. Biol.
Volume:329
Issue / Number:4
Start Page:699
End Page:710
Sequence Number of Article:1
Copyright:2003 Elsevier Science Ltd.
Review Status:Peer-review
Audience:Experts Only
Intended Educational Use:No
Abstract / Description:Ras specific GTPase activating proteins (GAPs), neurofibromin and p120GAP, bind GTP bound Ras and efficiently complement its active site. Here we present comparative data from mutations and fluorescence-based assays of the catalytic domains of both RasGAPs and interpret them using the crystal structures. Three prominent regions in RasGAPs, the arginine-finger loop, the phenylalanine-leucine-arginine (FLR) region and alpha7/variable loop contain structural fingerprints governing the GAP function. The finger loop is crucial for the stabilization of the transition state of the GTPase reaction. This function is controlled by residues proximal to the catalytic arginine, which are strikingly different between the two RasGAPs. These residues specifically determine the orientation and therefore the positioning of the arginine finger in the Ras active site. The invariant FLR region, a hallmark for RasGAPs, indirectly contributes to GTPase stimulation by forming a scaffold, which stabilizes Ras switch regions. We show that a long hydrophobic side-chain in the FLR region is crucial for this function. The alpha7/variable loop uses several conserved residues including two lysine residues, which are involved in numerous interactions with the switch I region of Ras. This region determines the specificity of the Ras-RasGAP interaction.
Free Keywords:Ras; GAP; p120GAP; NF1; neurofibromin
TRANSITION-STATE ANALOG; GAP-RELATED DOMAIN; TYPE-1 NF1 GENE; SIGNAL-TRANSDUCTION; ARGININE-FINGER; ONCOGENIC RAS; TUMOR PREDISPOSITION; PLECKSTRIN HOMOLOGY; LEARNING-DEFICITS; ALUMINUM FLUORIDE
External Publication Status:published
Document Type:Article
Communicated by:Jürgen Block
Affiliations:MPI für molekulare Physiologie/Abteilung I - Strukturelle Biologie/AG Rho-verwandte GTPasen: PD Dr. Mohammad Reza Ahmadian
External Affiliations:European Mol Biol Lab, Struct & Computat Biol Programme, D-69117 Heidelberg, Germany
Identifiers:URL:http://dx.doi.org/10.1016/S0022-2836(03)00514-X [article locator with full text links]
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