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FRISC: The Faculty Research Interests Science Comparator |
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Professor of Physiology
Biological Chemistry
Integrative Biology
Office: (214) 648-3308
FAX: (214) 648-4771
Email: gdemar@mednet.swmed.edu
Our laboratory studies the biochemical mechanisms and physiological functions of
intracellular protein degradation. The regulated degradation of cellular proteins controls
many cellular processes (such as the cell cycle, oncogenesis, transcription, development,
and flux of substrates through metabolic pathways) by determining levels of proteins that
control these processes. Regulated rates of global protein degradation also determine
whether developed tissues grow or atrophy. To understand the biochemistry, physiology and
pathology of protein degradation we study intracellular proteases, focusing on one called
the proteasome. The proteasome is the proteolytic component of the ubiquitin pathway,
which targets proteins for destruction by the proteasome by covalently modifying them with
a polyubiquitin chain.
The proteasome is found from bacteria to humans and has novel structural and functional
properties. It is an extremely large enzyme (Mr=700,000) composed of 28 subunits arranged
in a cylinder-shaped particle. In eukaryotes, these subunits represent the products of 14
distinct but homologous genes, which have no similarity to other proteases in nature. The
proteasome is normally an inactive enzyme because its multiple catalytic sites are located
within a hollow core of the cylinder and therefore are inaccessible to substrates. We have
identified and are studying a series of regulatory proteins that activate the proteasome
by binding to it and conformationally opening pores through which substrates can reach the
catalytic sites. These activators bind to the polyubiquitin chains that target protein
degradation, and then unfold the substrates and translocate them through the opened pores
by an ATP-dependent mechanism. The activators are themselves large multisubunit proteins,
whose structures, molecular mechanisms, and regulatory properties are the topics of
ongoing projects using biochemical, biophysical, molecular biological, and cell
physiological methods. Our goal is to understand how these proteins influence the function
and regulation of the proteasome, and to elucidate the physiological and pathological role
of the proteasome system in proteolytic pathways of intact cells.
Selected Publications:
DeMartino, GN and Slaughter, CA (1999) The proteasome. A novel protease regulated by
multiple mechanisms. J Biol Chem (In Press)
Wigley, WC, Fabunmi, RP, Lee, MG, Marino, CR, Muallem, S, DeMartino, GN and Thomas, PJ
(1999) Dynamic association of proteasomal machinery with the centrosome. J Cell Biol
145:481-490
Lin, L, DeMartino, GN and Greene, WC (1998) Cotranslational biogenesis of NF- k B p50 by the 26S proteasome. Cell 92:819-828
Lam YA, Xu W, DeMartino GN and Cohen RE (1997) Editing of ubiquitin conjugates by an
isopepidase in the 26S proteasome. Nature 385:737-740
Song, X, von Kampen, J, Slaughter, CA and DeMartino (1997) Relative functions of the a and b subunits of the proteasome
activator, PA28. J Biol Chem 272:27994-28000
Song X, Mott JD, von Kampen J, Pramanik K, Tanaka K, Slaughter CA and DeMartino GN
(1996) A model for the quaternary structure of the proteasome activator, PA28. J Biol
Chem 271:26410-26417
Page maintained by Stephanie
Robertson
Last updated: 17 Nov 2000
Extraction Method: Expand using Medical Synonyms-
Eliminated words list: MedlinePlus List
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Similarity Method: Weighted keyword count
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Database: Medline abstracts (1967 - Present)
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