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

ID: 15669.0, MPI für molekulare Physiologie / Sonstige wissenschaftliche Organisationseinheiten
The activation of RalGDS can be achieved independently of its Ras binding domain - Implications of an activation mechanism in Ras effector specificity and signal distribution
Authors:Linnemann, Thomas; Kiel, Christina; Herter, Peter; Herrmann, Christian
Research Context:Small GTPases
Date of Publication (YYYY-MM-DD):2002-03-01
Title of Journal:Journal of Biological Chemistry
Journal Abbrev.:J. Biol. Chem.
Issue / Number:10
Start Page:7831
End Page:7837
Sequence Number of Article:1
Review Status:Peer-review
Audience:Experts Only
Intended Educational Use:No
Abstract / Description:Small GTPases of the Ras family are major players of signal transduction in eukaryotic cells. They receive signals from a number of receptors and transmit them to a variety of effectors. The distribution of signals to different effector molecules allows for the generation of opposing effects like proliferation and differentiation. To understand the specificity of Ras signaling, we investigated the activation of RalGDS, one of the Ras effector proteins with guanine- nucleotide exchange factor activity for Ral. We determined the GTP level on RalA and showed that the highly conserved Ras binding domain (RBD) of RalGDS, which mediates association with Ras, is important but not sufficient to explain the stimulation of the exchange factor. Although a point mutation in the RBD of RalGDS, which abrogates binding to Ras, renders RalGDS independent to activated Ras, an artificially membrane-targeted version of RalGDS lacking its RBD could still be activated by Ras. The switch II region of Ras is involved in the activation, because the mutant Y64W in this region is impaired in the RalGDS activation. Furthermore, it is shown that Rap1, which was originally identified as a Ras antagonist, can block Ras- mediated RalGDS signaling only when RalGDS contains an intact RBD. In addition, kinetic studies of the complex formation between RalGDS-RBD and Ras suggest that the fast association between RalGDS and Ras, which is analogous to the Ras/Raf case, achieves signaling specificity. Conversely, the Ras.RalGDS complex has a short lifetime of 0.1 s and Rap1 forms a long- lived complex with RalGDS, possibly explaining its antagonistic effect on Ras.
External Publication Status:published
Document Type:Article
Communicated by:Jürgen Block
Affiliations:MPI für molekulare Physiologie/Abteilung I - Strukturelle Biologie/AG Struktur-Funktions-Beziehungen: PD Dr. Christian Herrmann
MPI für molekulare Physiologie/Abteilung I - Strukturelle Biologie/AG Klinische Pathobiologie: Dr. Peter Herter
Identifiers:URL:http://www.jbc.org/cgi/content/abstract/277/10/783... [abstract of this article with full text links]
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