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This demonstrates the crystal structure of PA28α; the paper shows that PA28α is a heptameric ring with a central cavity. A model of how PA28 associates with the proteasome is presented which can be used to further characterize the interaction between PA28 and the 20S proteasome.
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•] revealed that mutations which cause a defect in heteromer assembly mapped to the central portion of the regulator whereas mutations affecting binding to and/or activation of the proteasome localize to the bottom part of the PA28 structure. PA28 subunits which bind, but do not activate, the proteasome could serve as dominant-negative mutants useful for studying the role of PA28 in antigen presentation in vivo
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•] revealed that mutations which cause a defect in heteromer assembly mapped to the central portion of the regulator whereas mutations affecting binding to and/or activation of the proteasome localize to the bottom part of the PA28 structure. PA28 subunits which bind, but do not activate, the proteasome could serve as dominant-negative mutants useful for studying the role of PA28 in antigen presentation in vivo.
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This study shows that complexes consisting of 20S proteasomes together with PA28 and the ATPase complex co-immunoprecipitate. Thus it seems likely that ubiquitinated protein degradation, which requires the ATPase complex, can be modulated by PA28
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••], it is suggested here that precursor peptides are degraded in a two-step process to generate MHC-binding peptides. Endoproteolytic cleavage of the carboxy-terminal ends of peptides can be inhibited by lactacystin and thus involves the proteasome. By contrast, the amino-terminal end is generated via trimming by aminopeptidases, in particular leucine aminopeptidase. Since leucine aminopeptidase is upregulated by IFN-γ [42], this enzyme might be generally involved in antigen processing.
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••], it is suggested here that precursor peptides are degraded in a two-step process to generate MHC-binding peptides. Endoproteolytic cleavage of the carboxy-terminal ends of peptides can be inhibited by lactacystin and thus involves the proteasome. By contrast, the amino-terminal end is generated via trimming by aminopeptidases, in particular leucine aminopeptidase. Since leucine aminopeptidase is upregulated by IFN-γ [42], this enzyme might be generally involved in antigen processing.
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Luckey CJ, King GM, Marto JA, Venketeswaran S, Maier BF, Crotzer VL, Colella TA, Shabanowitz J, Hunt DF, Engelhard VH Proteasomes can either generate or destroy MHC class I epitopes: evidence for nonproteasomal epitope generation in the cytosol. J Immunol. 161:1998;112-121.
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48
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This study shows that an overexpressed, mutated, inactive LMP2 subunit incorporated into the proteasomal complex results in reduced overall peptide production. Surprisingly, however, LMP2 inactivation increased the production of a particular epitope. Targeted mutation of proteasome subunits could facilitate the understanding of the functional consequences of IFN-γ-induced structural changes.
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Schmidtke G, Eggers M, Ruppert T, Groettrup M, Koszinowski UH, Kloetzel P-M Inactivation of a defined active site in the mouse 20S proteasome complex enhances major histocompatibility complex class I antigen presentation of a murine cytomegalovirus protein. J Exp Med. 187:1998;1641-1646. This study shows that an overexpressed, mutated, inactive LMP2 subunit incorporated into the proteasomal complex results in reduced overall peptide production. Surprisingly, however, LMP2 inactivation increased the production of a particular epitope. Targeted mutation of proteasome subunits could facilitate the understanding of the functional consequences of IFN-γ-induced structural changes.
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A proteolytic system that compensates for loss of proteasome function
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This study shows that EL-4 cells developed resistance to inactivation of the proteasome that is caused by irreversible inhibitors. As a compensatory mechanism, a high-molecular-weight protease seems to be upregulated which might be similar to the one described in [52]. Since this protease seems to be able to provide all proteasomal functions, including peptide production for antigen presentation by MHC class I, it might also normally contribute to antigen processing.
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Glas R, Bogyo M, McMaster JS, Gaczynska M, Ploegh HL A proteolytic system that compensates for loss of proteasome function. Nature. 392:1998;618-622. This study shows that EL-4 cells developed resistance to inactivation of the proteasome that is caused by irreversible inhibitors. As a compensatory mechanism, a high-molecular-weight protease seems to be upregulated which might be similar to the one described in [52]. Since this protease seems to be able to provide all proteasomal functions, including peptide production for antigen presentation by MHC class I, it might also normally contribute to antigen processing.
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A new large proteolytic complex distinct from the proteasome is present in the cytosol of fission yeast
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Osmulski PA, Gaczynska M A new large proteolytic complex distinct from the proteasome is present in the cytosol of fission yeast. Curr Biol. 8:1998;1023-1026.
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