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FRISC: The Faculty Research Interests Science Comparator |
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Assistant Professor of Pharmacology
Molecular
Biophysics
Email: chooky@rockvax.rockefeller.edu
In eukaryotic cells, signal-mediated macromolecular transport between the
nucleus and the cytoplasm is an integral part of many processes such as gene
expression, signal transduction and cell cycle progression. Direction of
transport through the NPC is determined by a signal in the cargo protein:
the NLS directs proteins into the nucleus whereas the NES directs proteins into
the cytoplasm. The NLS/NES is recognized by proteins of the Karyopherin b
(Kap b ) family. Interactions between Kap b
and NPC proteins (nucleoporins) then target the substrate for transport through
the NPC.
An important aspect of research in our laboratory will entail structural
characterization of nuclear transport factor-substrate complexes to identify and
characterize non-classical nuclear localization and export signals (NLS, NES).
Most Kap b s have been characterized as either import
or export factors based on the identification of their substrates. To
date, no structural information is available for export systems. We will
focus our efforts in this area on the structure determination of Kap-export
substrate-RanGTP complexes such as Crm1-NES-Ran, Cas-Kap a -Ran
and Los1–tRNA-Ran. Structures of these complexes will allow us to
understand the molecular basis and requirements of nuclear export and provide
insights into mechanistic distinctions between nuclear import and export.
Recent evidence also suggests that some Kap b s may
mediate bidirectional transport. A bidirectional nuclear transporter,
Kap142/Msn5p, provides opportunities to explore the structural determinants of
transport directions that exist within the single Kap b
polypeptide through structural analysis and comparison of its export and import
complexes. Knowledge of the sequence and structural requirements for both
Kap142-mediated import and export could be used to predict and search for other
Kap b s with the capacity for bidirectional nuclear
transport. More generally, research on Kap-substrate complexes will
delineate molecular requirements for specific transport pathways, and more
importantly, will provide a means of understanding and classifying
macromolecular traffic patterns across the nuclear envelope.
The second facet of research in our laboratory will focus on structural and
biochemical analysis of the NPC to understand its biogenesis, transport
properties and regulation. The NPC is a very large (125 MDa, 20 times
larger than a ribosome) and complex (multiple copies of ~50 different proteins)
subcellular structure. The NPC is disassembled into discrete subcomplexes
both in vitro by biochemical extraction, and also in vivo during mitosis. Structural studies of biochemically
obtained and mitotic NPC subcomplexes will be carried out to understand the
structure of the NPC and the regulation of its assembly/disassembly during the
cell cycle. This will lead to an understanding of how this massive
subcellular structure responds to events such as cell cycle progression and
extracellular stimulation. Thus through a combination of structural,
biochemical and cell biological analyses of nuclear transport and the NPC, we
will be able to explore how soluble transport factors and the NPC organize
nucleocytoplasmic transport to coordinate cellular functions and how cellular
events regulate structure and functions of the NPC.
Selected
Publications
Chook, Y.M., Jung, A. and Blobel, G. Mechanisms for Ran-mediated substrate
dissociation in the karyopherin-b2 nuclear import pathway. Manuscript in
preparation.
Chook, Y.M. and Blobel, G. (2001) Karyopherins and nuclear import. Current
Opinions in Structural Biology 11(6). Publication date December, 2001.
Chook, Y.M., Cingolani, G., Conti, E., Stewart, M., Vetter, I., Wittinghofer,
A. (1999) Pictures in cell biology. Structures of nuclear-transport components. Trends
in Cell Biol. 9(8), 310-311.
Chook, Y.M. and Blobel, G. (1999) Structure of the nuclear transport complex
karyopherin-b2-RanoGppNHp. Nature 399, 230-237.
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Last updated: 26 Sep 2001
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