Peptides for Presentation Are Generated by Protease Complexes Called Proteasomes

Intracellular proteins are degraded into short peptides by a cy-tosolic proteolytic system present in all cells. Those proteins targeted for proteolysis often have a small protein, called ubiquitin, attached to them (Figure 8-5a). Ubiquitin-protein conjugates can be degraded by a multifunctional protease complex called a proteasome. Each proteasome is a large (26S), cylindrical particle consisting of four rings of protein subunits with a central channel of diameter 10-50 A. A proteasome can cleave peptide bonds between 2 or 3 different amino acid combinations in an ATP-dependent process (Figure 8-5b). Degradation of ubiquitin-protein complexes is thought to occur within the central hollow of the proteasome.

Experimental evidence indicates that the immune system utilizes this general pathway of protein degradation to produce small peptides for presentation with class I MHC molecules. The proteasomes involved in antigen processing include two subunits encoded within the MHC gene cluster, LMP2 and LMP7, and a third non-MHC protein, LMP10 (also called MECL-1). All three are induced by increased levels of the T-cell cytokine IFN-7. The peptidase activities of proteasomes containing LMP2, LMP7, and LMP10 preferentially generate peptides that bind to MHC class I molecules. Such proteasomes, for example, show increased hydrolysis of peptide bonds that follow basic and/or hydrophobic

Ubiquinating enzyme complex + ubiquitin >

COOH ATP

e-amino group on lysine side chain

Ubiquinating enzyme complex + ubiquitin >

COOH ATP

COOH

COOH

Proteolytic enzyme subunit

Proteolytic enzyme subunit

COOH Protein

Proteasome

FIGURE 8-5

COOH Protein

Proteasome

Peptides

FIGURE 8-5

Cytosolic proteolytic system for degradation of intracellular proteins. (a) Proteins to be degraded are often covalently linked to a small protein called ubiquitin. In this reaction, which requires ATP, a ubiquinating enzyme complex links several ubiquitin molecules to a lysine-amino group near the amino terminus of the protein. (b) Degradation of ubiquitin-protein complexes occurs within the central channel of proteasomes, generating a variety of peptides. Proteasomes are large cylindrical particles whose subunits catalyze cleavage of peptide bonds.

residues. As described in Chapter 7, peptides that bind to class I MHC molecules terminate almost exclusively with hy-drophobic or basic residues.

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