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Gene Expression-178

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Protein-12

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Chapter category: Signal Transduction

Ubiquitination and TRAF Signaling

Chapter authors:
Gabriel Pineda, Chee-Kwee Ea and Zhijian J. Chen

The Ubiquitin-Proteasome Pathway Ubiquitin (Ub) is a highly conserved small polypeptide that is ubiquitously expressed in all eukaryotic cells. The best-known function of ubiquitin is to target protein degradation through covalent attachment of this polypeptide on protein substrates.1-3 This covalent modification, known as ubiquitination, is carried out via a three-step enzymatic cascade. In the first step, Ub is activated by the Ub-activating enzyme (E1) in an ATP-dependent reaction to form an E1-Ub thioester. In the second step, the activated Ub is transferred to a cysteine residue in the active site of a Ub-conjugating enzyme (Ubc or E2) to form an E2-Ub thioester. Finally, in the presence of a Ub-protein ligase (E3), ubiquitin is conjugated to a protein substrate by forming an isopeptide bond between the carboxyl terminus of ubiquitin and the e-amino group of a lysine residue on the protein target. After Ub is conjugated to a protein substrate, Ub itself can be conjugated by another Ub through one of its seven lysines, typically lysine-48. This process reiterates itself in a highly processive manner to form a polyubiquitin chain, which is then recruited to a large ATP-dependent protease complex called the 26S proteasome. The polyubiquitinated protein substrates are degraded inside the proteasome, whereas the polyubiquitin chains are cleaved to monomeric ubiquitin, which is recycled. The 26S proteasome is composed of the 20S catalytic core and 19S regulatory particle.4 The 20S proteasome is a cylinder-like structure formed by four rings, each containing seven subunits. These subunits form an enclosed proteolytic chamber within which the catalytic residues reside. This chamber is impermeable to proteins, except for a narrow channel that connects to the 19S proteasome, which gates the entry of protein substrates. The 19S complex can be further separated into a base and a lid. The base contains multiple ATPase subunits, which presumably function to unfold ubiquitinated protein substrates and propel the unfolded polypeptides through the narrow channel into the catalytic chamber of the proteasome. The lid contains nonATPase subunits, some of which bind to polyubiquitin chains and recruit polyubiquitinated proteins to the proteasome.

Gabriel Pineda
Department of Molecular Biology, University of Texas Southwestern Medical Center

Chee-Kwee Ea
Department of Molecular Biology, University of Texas Southwestern Medical Center

Zhijian J. Chen
Department of Molecular Biology, University of Texas Southwestern Medical Center

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