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▲ FIGURE 3-13 Ubiquitin-mediated proteolytic pathway. (a) Enzyme E1 is activated by attachment of a ubiquitin (Ub) molecule (step 1) and then transfers this Ub molecule to E2 (step 2). Ubiquitin ligase (E3) transfers the bound Ub molecule on E2 to the side-chain —NH2 of a lysine residue in a target protein (step 3). Additional Ub molecules are added to the target protein by repeating steps 1 - 3, forming a polyubiquitin chain that directs the tagged protein to a proteasome (step 4). Within this large complex, the protein is cleaved into numerous small peptide fragments (step 5). (b) Computer-generated image reveals that a proteasome has a cylindrical structure with a cap at each end of a core region. Proteolysis of ubiquitin-tagged proteins occurs along the inner wall of the core. [Part (b) from W. Baumeister et al., 1998, Cell 92:357; courtesy of W. Baumeister.]

■ Formation of a peptide bond between the ubiquitin molecule bound to E2 and a lysine residue in the target protein, a reaction catalyzed by ubiquitin ligase (E3)

This process is repeated many times, with each subsequent ubiquitin molecule being added to the preceding one. The resulting polyubiquitin chain is recognized by a proteasome, another of the cell's molecular machines (Figure 3-13b). The numerous proteasomes dispersed throughout the cell cytosol proteolytically cleave ubiquitin-tagged proteins in an ATP-dependent process that yields short (7- to 8-residue) peptides and intact ubiquitin molecules.

Cellular proteins degraded by the ubiquitin-mediated pathway fall into one of two general categories: (1) native cy-tosolic proteins whose life spans are tightly controlled and (2) proteins that become misfolded in the course of their synthesis in the endoplasmic reticulum (ER). Both contain sequences recognized by the ubiquitinating enzyme complex. The cyclins, for example, are cytosolic proteins whose amounts are tightly controlled throughout the cell cycle. These proteins contain the internal sequence Arg-X-X-Leu-Gly-X-Ile-Gly-Asp/Asn (X can be any amino acid), which is recognized by specific ubiquitinating enzyme complexes. At a specific time in the cell cycle, each cyclin is phosphorylated by a cyclin kinase. This phosphorylation is thought to cause a conformational change that exposes the recognition sequence to the ubiquitinating enzymes, leading to degradation of the tagged cyclin (Chapter 21). Similarly, the misfolding of proteins in the endoplasmic reticulum exposes hydrophobic sequences normally buried within the folded protein. Such proteins are transported to the cytosol, where ubiquitinat-ing enzymes recognize the exposed hydrophobic sequences.

The immune system also makes use of the ubiquitin-mediated pathway in the response to altered self-cells, particularly virus-infected cells. Viral proteins within the cytosol of infected cells are ubiquitinated and then degraded in pro-teasomes specially designed for this role. The resulting anti-genic peptides are transported to the endoplasmic reticulum, where they bind to class I major histocompatibility complex (MHC) molecules within the ER membrane. Subsequently, the peptide-MHC complexes move to the cell membrane where the antigenic peptides can be recognized by cytotoxic T lymphocytes, which mediate the destruction of the infected cells.

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