The overall goal of this proposal is to understand at a molecular level the functions of the RAN GTPase, and of Ran-interacting proteins, in nuclear protein import and export. This goal will be approached via the following specific aims: 1. Critically test the hypothesis that Ran enters and exits the nucleus as a component of the transport receptor complex. 2. Examine central aspects of the transport mechanism: determine whether nuclear Ran:GTP is the only energy source required for import and export; and test the hypothesis that Ran binding to RanBP2 is a necessary step in nuclear protein import. 3. Determine whether the Ran binding protein, RanBP1, shuttles in and out of the nucleus, and functions as a chaperone for importin-beta export. 4. Identify the novel nuclear import signal on Hrb3, a new Ran binding protein, and clone the receptor for this signal. These goals will be achieved using a variety of technologies including micro-injection of recombinant proteins and in vitro transport assays. Nuclear transport is a key regulatory step in signal transduction pathways that modulate gene expression and the cell cycle. Nuclear transport is also targetted by several clinically- important viruses, such as HIV, to ensure preferential replication of the viral genome, and synthesis of new virions. Understanding the detailed mechanism of nuclear protein transport may therefore provide novel targets for anti-viral therapies.
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