Of the 600+ known proteases identified to date in mammals, a significant percentage is involved or implicated in pathogenic and cancer processes. The dipeptidyl peptidase IV (DPIV) gene family, comprising four enzyme members [DPIV (EC 3.4.14.5), fibroblast activation protein, DP8 and DP9] and two nonenzyme members [DP6 (DPL1) and DP10 (DPL2)], are interesting in this regard because of their multiple diverse functions, varying patterns of distribution/localization and subtle, but significant, differences in structure/substrate recognition. In addition, their engagement in cell biological processes involves both enzymatic and nonenzymatic capabilities. This article examines, in detail, our current understanding of the biological involvement of this unique enzyme family and their overall potential as therapeutic targets.
Dipeptidyl peptidase IV (DPPIV) is an atypical serine protease that modifies the biological activities of certain chemokines and neuropeptides. In addition, human DPPIV, also known as the T‐cell activation antigen CD26, binds adenosine deaminase (ADA) to the T‐cell surface, thus protecting the T‐cell from adenosine‐mediated inhibition of proliferation. Mutations were engineered into DPPIV (five point, 16 single point and six deletion mutations) to examine the binding of ADA and 19 monoclonal antibodies. Deletions of C‐terminal residues from the 738‐residue extracellular portion of DPPIV showed that the 214 residues C‐terminal to Ser552 were not required for ADA binding and that peptidase activity could be ablated by deletion of 20 residues from the C‐terminus. Point mutations at either of two locations, Leu294 and Val341, ablated ADA binding. Binding by six anti‐DPPIV antibodies that inhibited ADA binding was found to require Leu340 to Arg343 and Thr440/Lys441 but not the 214 residues C‐terminal to Ser552. The 13 other antibodies studied bound to a truncated DPPIV consisting of amino acids 1–356. Therefore, the binding sites on DPPIV of ADA and antibodies that inhibit ADA binding are discontinuous and overlapping. Moreover, the 47 and 97 residue spacing of amino acids in these binding sites concords with their location on a β propeller fold consisting of repeated β sheets of about 50 amino acids.
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