George N. DeMartino, Ph.D. Professor Voice (214) 645-6024 Fax (214) 645-6019 Room ND12.124AA George.DeMartino@UTSouthwestern.edu The University of Texas Southwestern Medical Center at Dallas Department of Physiology 5323 Harry Hines Boulevard Dallas, TX  75390-9040 DeMartino Lab

Biochemistry and Molecular Biology Graduate Program
Integrative Biology Graduate Program

Intracellular protein degradation by the ubiquitin-proteasome system

Our laboratory studies the biochemical mechanisms and physiological functions of intracellular protein degradation. The degradation of cellular proteins is an extensive process that plays a critical role in the regulation of levels of individual proteins and in the net growth or atrophy of tissues. To understand the biochemistry, physiology and pathology of this process we study intracellular proteases that are components of key proteolytic pathways. We are concentrating on one protease called the proteasome. The proteasome is found from bacteria to humans and has unusual 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's multiple catalytic sites are located in the interior of the cylinder and, unlike all other known protease active sites, are comprised of threonine residues. These multiple catalytic sites function in a coordinated fashion to processively degrade proteins by a mechanism that channels peptide intermediates.

We have shown that the proteasome is an obligatory component of the ubiquitin-dependent proteolytic pathway. This pathway selectively degrades many intracellular proteins and is involved in a variety of cellular functions including: the regulated degradation of cell cycle control proteins (such as cyclins), the activation of transcription factors (such as NFk B), antigen processing, and bulk protein turnover under conditions of tissue atrophy. Substrates for this system are first covalently attached to a polyubiquitin chain, which targets the protein for destruction by the proteasome. However, we have also shown that the proteasome's role in this process depends on specific regulatory proteins that bind to its terminal rings to form super-molecular weight complexes with specific catalytic and regulatory features. We have purified a series of these large, multisubunit regulatory proteins, and are currently studying their structures, functions and regulation using biochemical, 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 role of the proteasome system in proteolytic pathways of intact cells.

Publications