Rab5 Activation by the Vps9 Domain

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Rab5 Activation by the Vps9 Domain

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Title: Rab5 Activation by the Vps9 Domain
Author: Carney, Darren Scott
Abstract: The movement of proteins through the endocytic pathway is a complex and highly regulated process. Not only is this pathway used to internalize cellular nutrients, but it is also used to modulate a cell's response to extracellular stimuli. Internalization and subsequent trafficking of transmembrane receptor proteins that receive these signals from the external milieu play an essential role in establishing and maintaining cellular homeostasis. As key regulators of the early stages the endocytic pathway, the small GTPases of the Rab5 family serve an essential function in integrating intracellular protein traffic and these cell signaling events. Rab5 proteins exert their influence on protein trafficking only when bound to GTP. A large family of proteins containing a conserved domain (Vps9) activate Rab5 by promoting the release of GDP and reloading of GTP. These nucleotide exchange factors contain additional domains which link them to specific cellular locations or signaling cascades. The multiplicity of these Rab5 proteins and exchange factors raises the question of how these proteins specifically interact to regulate individual trafficking events. To investigate this specificity, the three Rab5 proteins of Saccharomyces cerevisiae, Vps21, Ypt52 and Ypt53, and the two yeast Vps9 domain-containing proteins, Vps9 and Muk1, were analyzed. This analysis identified previously unappreciated roles for Ypt53 and Muk1 in a relatively late stage of endocytosis. A mutational analysis of Vps9 identified several residues important for Vps9 domain function and shed light on a possible intramolecular regulation of this domain by the carboxy-terminal ubiquitin-binding CUE domain. Finally, structural studies of the Rab5/Vps9 domain complex were initiated to gain a better understanding of the molecular mechanisms by which Rab5 proteins interact with and are activated by the Vps9 domain.
URI: http://hdl.handle.net/2152.5/252
Date: 2007-05-21

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