Abstract
Dipeptidyl peptidase I (DPPI) is a lysosomal cysteine protease that catalyzes the sequential removal of dipeptides from the amino termini of various protein substrates. We have isolated a cDNA coding for murine DPPI from mouse thymus and spleen cDNA libraries. The deduced amino acid sequence codes for a protein of 462 amino acid residues; comparison of this deduced sequence with that of rat and human DPPI revealed 90.1% and 77.8% identity, respectively. Using DPPI cDNA, we obtained two BAC (Bacterial Artificial Chromosome) clones that contained the murine DPPI locus. The DPPI gene consists of seven exons and 6 introns, and spans approximately 20 kilobases. Using fluorescence in situ chromosome hybridization, we localized murine DPPI to chromosome 7D3-E1.1. We determined that DPPI protein is widely distributed in mouse tissues, although its relative abundance varies from tissue to tissue. In contrast to previous reports, we show here that DPPI mRNA and protein levels and enzymatic activity are unchanged during in vitro T cell activation, implying that this enzyme is not rate-limiting for granzyme processing.
Highlights
Dipeptidyl peptidase I (DPPI,1 or cathepsin C) is a lysosomal cysteine protease that belongs to the papain superfamily of proteases [1, 2]
Several reports have suggested that DPPI activity, present in a wide variety of tissues, is significantly higher in cytotoxic lymphocytes and myeloid cells [13,14,15]; in these cells, DPPI localizes to the secretory granule compartment and may be the major enzyme responsible for processing serine proteases from the proenzyme form to the catalytically active form [14, 15]
Unlike most other cysteine proteases, which are small monomeric proteins with molecular masses of 20 –30 kDa, DPPI exists as an oligomeric enzyme of about 200 kDa, as determined by gel filtration [4, 6, 26, 27]
Summary
Vol 272, No 16, Issue of April 18, pp. 10695–10703, 1997 Printed in U.S.A. Molecular Cloning, Chromosomal Localization, and Expression of Murine Dipeptidyl Peptidase I*. DPPI is capable of sequentially removing dipeptides from the amino termini of various peptides and protein substrates [3,4,5,6,7] and, along with other cysteine proteases, is thought to play an important role in intracellular protein degradation and turnover [4, 8, 9] This enzyme has other postulated functions, including involvement in cell growth [10], neuraminidase activation [11], and platelet factor. Most studies suggest that the monomeric subunit is composed of a heavy chain and light chain (both originating from the mature region of the protein); a recent report presented evidence that active human DPPI consists of four identical subunits, each composed of three different polypeptide chains, two of them disulfide-linked [28].
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