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Altered properties of the branched chain amino acid-preferring activity contribute to increased cleavages after branched chain residues by the "immunoproteasome."

Authors
Cardozo-C; Kohanski-RA
Source
J Biol Chem 1998 Jul; 273(27):16764-16770
NIOSHTIC No.
20030540
Abstract
The multicatalytic proteinase complex (MPC, proteasome) is assembled from 14 nonidentical protein subunits. It expresses five distinct proteolytic activities, including a chymotrypsin-like activity, cleaving after hydrophobic residues, and a branched chain amino acid-preferring component (BrAAP), cleaving preferentially after branched chain residues. Exposure of cells to interferons leads to replacement of the X, Y, and Z subunits by the LMP2, LMP7, and MECL1 subunits. This "immunoproteasome" is critical to processing of certain antigens. The enzymatic basis for enhanced antigen processing has not been determined. To gain insight into this question, we examined sites and relative rates of cleavage of bonds in denatured, reduced, carboxyamidomethylated lysozyme, a 129-amino acid protein, by MPC from bovine spleen, in which the X, Y, and Z subunits are replaced by LMP2, LMP7, and MECL1. We compared cleavages to those catalyzed by MPC from bovine pituitary, which contains only the X, Y, and Z subunits. We found marked increases in the rates and number of cleavages after branched chain residues in reduced, carboxyamidomethylated lysozyme by the spleen MPC. This was largely due to accelerated cleavages of bonds after a Phi-X-Br motif, where Phi is a hydrophobic residue, X is a small neutral or polar residue, and Br is a branched chain residue. Inhibitors with these structural properties were selective and potent inhibitors of the BrAAP activity of the spleen MPC. The above findings indicate that alterations in activity and substrate specificity of the BrAAP activity are important factors underlying the altered cleavages after hydrophobic residues associated with incorporation of interferon-inducible subunits. The potential relevance of the findings to antigen processing functions of MPC is discussed.
Keywords
Amino-acids; Metabolism; Proteins; Animals; Enzymology; Antigens; Exposure-assessment
CODEN
JBCHA3
Publication Date
19980703
Document Type
Journal Article
Email Address
c_cardozo@smtplink.mssm.edu
Funding Type
Grant
Fiscal Year
1998
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-K01-OH-002835
Issue of Publication
27
ISSN
0021-9258
Source Name
Journal of Biological Chemistry
State
NY
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