The Molecular Mechanism of Nuclear Protein Import

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• Dr Murray Stewart, MRC-LMB, Cambridge
• Friday 27 February 2009, 14:15-15:15
• Pippard Lecture Theatre, Cavendish Laboratory.

If you have a question about this talk, please contact Jurij Kotar.

The nuclear import of proteins through nuclear pore complexes (NPCs) illustrates how a complex biological function can be generated by a spatially and temporally organized cycle of interactions between cargoes, carriers and the Ras family GTPase, Ran. Recent work has given considerable insight into this process, especially about how interactions are coordinated and the basis for the molecular recognition that underlies the process. Overall nuclear protein import can be considered in terms of three steps: first, a cargo:carrier complex is formed in the cytoplasm; next, the cargo:carrier complex is translocated through the NPC transport channel; and finally the cargo is dissociated from the carrier in the nucleus and the carrier is recycled to the cytoplasm. The assembly and disassembly steps are orchestrated by the nucleotide state of the Ran GTPase. Thus, cytoplasmic RanGDP facilitates assembly of the cargo:carrier complex, whereas nuclear RanGTP dissociates it. The nucleotide state of Ran is determined by its GTPase activating protein (RanGAP) being located in the cytoplasm while its guanine nucleotide exchange factor (RanGEF or RCC1 ) is nuclear. Translocation of the cargo:carrier complex through the pore does not require energy and functions to equilibrate the complex between the cytoplasmic and nuclear compartments; transport is instead driven by import complex dissociation in the nucleus with the energy deriving from GTP hydrolysis ultimately being liberated in the cytoplasm. Overall, nuclear protein import is an example of a process driven by rectified Brownian motion (a “thermal ratchet”) with energy being used primarily for sorting, generating a biological version of Maxwell’s demon. Although considerable progress has been made in identifying and characterizing the molecular interactions in the soluble phase that drive the nuclear protein import cycle, understanding the precise mechanism of translocation through NPCs and how the NPC generates a barrier to other macromolecules remain major challenges.

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