The long-term goals of research in the DeMartino laboratory are to understand the biochemical mechanisms and the physiological functions and regulation of intracellular protein degradation. Cells utilize protein degradation to control many normal cellular processes including transcription, cell cycle progression, signal transduction, flux of substrates through metabolic pathways, adaptation to stress, protein quality control, net growth and atrophy, immune function, circadian rhythm, and apoptosis. Moreover, dysfunction of normal protein degradation leads to numerous human pathologies including many types of cancer, tissue wasting diseases, and neurodegenerative diseases.
Most protein degradation in eukaryotic cells is catalyzed by the ubiquitin-proteasome system. This multi-component proteolytic system targets proteins for destruction by covalently modifying them with a polymer of ubiquitin, a small, highly conserved protein. Polyubiquitin-modified proteins are selectively recognized and degraded by the 26S proteasome, a 2,400,000-dalton ATP-dependent protease complex.
Our research focuses on two general topics. First, we seek to determine how the 26S proteasome selectively degrades ubiquitin-modified proteins. This work includes defining the detailed molecular structure of the 26S proteasome and elucidating the precise roles of each of its 32 different subunits in accomplishing energy-dependent proteolysis. Second, we seek to understand how the proteasome functions in intact cells and how cellular proteasome function is regulated in normal and pathological states. Our research will provide a fundamental understanding of how the proteasome works as an energy-dependent molecular machine, and the roles of proteasome-dependent protein degradation in health and disease.
RESEARCH INTERESTS
Intracellular protein degradation
Proteasome
Ubiquitin and ubiquitin-like proteins
Muscle growth and atrophy
Calpains
RECENT PUBLICATIONS
Wahlman, J, DeMartino, GN, Skach, WR, Bulleid, NJ, Brodsky, JL and Johnson, AE, "Real-time detection of ERAD substrate retro-translocation in a mammalian in vitro system." Cell, 129:943-955, 2007
Liu, C, Li, X, Thompson, D, Wooding, K, Chang, T, Tang, Z, Yu, H, Thomas, PJ, and DeMartino, GN, "ATP binding and ATP hydrolysis play distinct roes in the function of 26S proteasome." Mol Cell, 24:39-50, 2006
Wojcik C, Rowicka, M, Kudlicki, A, Nowis, D, Adams, GM, Kujawa, M, and DeMartino GN, "VCP is a regulator of ER stress involved in the degradation of multiple substrates of the ubiquitin-proteasome system in mammalian cells." Mol Biol Cell, 17:4606-4618, 2006
Wojcik, C, Yano, M, and DeMartino, GN, "RNA interference of VCP reveals multiple cellular roles linked to ubiquitin-proteasome dependent proteolysis." J Cell Sci, 117:281-92, 2004
SIGNIFICANT PUBLICATIONS
DeMartino, GN and Goldberg, AL, "Identification and partial purification of an ATP-stimulated alkaline protease in rat liver." J Biol Chem, 254:3712-3715, 1979
McGuire, MJ, McCullough, ML, Croall, DE, and DeMartino, GN, "The latent form of macropain (high molecular weight multicatalytic protease) restores ATP-dependent proteolysis to cell-free extracts of BHK fibroblasts pretreated with antimacropain antibodies." Biochim Biophys Acta, 995:181-186, 1989
Ma, C-P, Slaughter, CA, and DeMartino, GN, "Identification, purification and characterization of a protein activator (PA28) of the 20S proteasome (macropain)." J Biol Chem, 267:10515-10523, 1992
Ma, C-P, Vu, JH, Proske, RJ, Slaughter, CA, and DeMartino, GN, "Identification, purification, and characterization of a high molecular weight ATP-dependent activator (PA700) of the 20S proteasome." J Biol Chem, 269:3539-3547, 1994
Liu, CW, Corboy, MJ, DeMartino, GN, and Thomas, PJ, "Endoproteolytic activity of the proteasome." Science, 299:408-411, 2003
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