Ala and conserved active site residues promote fibroblast activation protein endopeptidase activity via distinct mechanisms of transition state stabilization
Biochemistry, ISSN: 0006-2960, Vol: 46, Issue: 15, Page: 4598-4605
2007
- 31Citations
- 41Captures
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Metrics Details
- Citations31
- Citation Indexes31
- 31
- CrossRef24
- Captures41
- Readers41
- 41
Article Description
Fibroblast activation protein (FAP) and dipeptidyl peptidase-4 (DPP-4) are highly homologous serine proteases of the prolyl peptidase family and therapeutic targets for cancer and diabetes, respectively. Both proteases display dipeptidyl peptidase activity, but FAP alone has endopeptidase activity. FAP Ala, which corresponds to DPP-4 Asp, is important for endopeptidase activity; however, its specific role remains unclear, and it is unknown whether conserved DPP-4 substrate binding residues support FAP endopeptidase activity. Using site-directed mutagenesis and kinetic analyses, we show here that Ala and five conserved active site residues (Arg, Glu, Glu, Tyr , and Asn) promote FAP endopeptidase activity via distinct mechanisms of transition state stabilization (TSS). The conserved residues provide marked TSS energy for both endopeptidase and dipeptidyl peptidase substrates, and structural modeling supports their function in binding both substrates. Ala also stabilizes endopeptidase substrate binding and additionally dictates FAP reactivity with transition state inhibitors, allowing tight interaction with tetrahedral intermediate analogues but not acyl-enzyme analogues. Conversely, DPP-4 Asp stabilizes dipeptidyl peptidase substrate binding and permits tight interaction with both transition state analogues. Structural modeling suggests that FAP Ala and DPP-4 Asp confer their contrasting effects on TSS by modulating the conformation of conserved residues FAP Glu and DPP-4 Glu. FAP therefore requires the combined function of Ala and the conserved residues for endopeptidase activity. © 2007 American Chemical Society.
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