The ubiquitin-proteasome pathway is
responsible for degradation of more than 80% of
intracellular proteins in eukaryotes. It plays important
roles in protein quality control by degrading damaged
proteins, and also controls a variety of cellular processes
by temporal degradation of critical regulatory proteins
involving in cell cycle progression, apoptosis, and
development. Failure of this system may cause numerous human
diseases, such as cancers, neurodegenerative diseases, and
inflammatory diseases.
Usually, proteins are modified by
polyubiquitin chain(s) by a cascade of enzymatic reactions
including ubiquitin activating enzyme (E1), ubiquitin
conjugating enzyme (E2), and ubiquitin protein ligase (E3).
Polyubiquitinated proteins are degraded by the 26S
proteasome, a 2.4 MDa complex composed of the 20S
proteolytic complex and the 19S (PA700) regulatory complex.
The 20S proteasome has a barrel-shaped structure arranged as
heptameric abba rings. The
catalytic sites are located in the central b
rings. The access into the catalytic sites is occluded by a
gate formed by interaction of N-termini of asubunits. The
gate can be opened by interaction with PA700, an 18-subunit
complex with multiple activities, including polyubiquitin
chain binding activity, deubiquitination activity, substrate
remodeling activity, chaperon-like activity, and ATPase
activity.
One of my laboratory's interests is to
understand mechanisms by which the ubiquitin-proteasome
pathway degrades proteins. For example, how the 26S
proteasome recognizes and selects polyubiquitinated
substrates, and then how the proteasome processes a
substrate for degradation. We use purified mammalian
proteasomes and a variety of substrates to answer these
questions by biochemical and biophysical approaches.
Another laboratory interest is to
understand molecular pathways for Parkinson disease (PD)
pathogenesis. We are interested in studying how and why
a-synuclein is aggregated in Lewy
bodies of PD brains, and what is the possible role of the
ubiquitin-proteasome pathway in PD pathogenesis. We use cell
biological, molecular biological and biochemical approaches
to explore these questions.
Selected Publications
Liu C-W., Millen L., Roman T., Novia R., Gilbert H. F., DeMartino G. N., Thomas P. J., (2002) "Conformational Remodeling of Proteasomal Substrate by PA700, the Regulatory Complex of the 26S Proteasome." J. Biol. Chem., 277, 26815-26820.
Liu C-W., Millen L., Roman T., Novia R., Gilbert H. F., DeMartino G. N., Thomas P. J., (2002) "Conformational Remodeling of Proteasomal Substrate by PA700, the Regulatory Complex of the 26S Proteasome." J. Biol. Chem., 277, 26815-26820.
Liu C-W., Corboy M., DeMartino G. N., Thomas P. J., (2003) "Endoproteolytic Activity of the Proteasome". Science, 299, 408-411.
Lee, R. J., Liu, C-W., Harty, C., McCracken, A., Römisch, K., DeMartino, G. N.,Thomas, P. J., and Brodsky, J. L. (2004) "The 19S (PA700) Cap of the 26S Proteasome is Sufficient to Retro-Translocate and Deliver a Soluble Polypeptide for ER Associated Degradation (ERAD)". EMBO J., 23, 2206-2215.
Liu C-W., Giasson B. I., Lewis K., Lee V. M., DeMartino G. N., Thomas P. J., (2005) "A Precipitating Role for Truncated a -synucleins and the Proteasome in a -Synuclein Aggregation: Implications for Pathogenesis of asynucleinopathies". J. Biol. Chem., 280, 22670-22678.
Liu, C-W., Li, X-H., Thompson, D., Wooding, K., Chang, T-L., Tan, Z., Yu H., Thomas, P. J., and DeMartino, G. N., (2006) "ATP Binding and ATP Hydrolysis Play Distinct Roles in the Function of 26S Proteasome." Mol. Cell., in press.
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