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Dipeptidyl peptidase (DP) 8 belongs to the dipeptidyl peptidase IV gene family. DP8 has been implicated in immune function and asthma, although its biological function is yet unknown. Structures of the homologs, fibroblast activation protein (FAP) and DPIV, are known but the DP8 structure is yet to be resolved. To help characterise the DP8 substrate pocket, mutants of residues lining the pocket were produced at DP8 D772 , DP8 Y315 , DP8 H434  and DP8 D435  and assessed by substrate kinetics and size-exclusion chromatography. Mutations of DP8 D772A/E/S/V  affected catalysis but did not confer endopeptidase activity. Mutations of DP8 H434F , DP8 D435F  and DP8 Y315F  reduced catalytic activity. Furthermore, mutations to DP8 D772A/E/S/V , DP8 H434F , DP8 D435F  and DP8 Y315F  affected dimer stabilisation. Homology modelling of DP8 using DPIV and FAP crystal structures suggested that DP8 D772 , DP8 H434  and DP8 D435  were located at the edge of the S2 catalytic pocket, contributing to the junction between the alpha-beta hydrolase and beta-propeller domains. This study provides insights into how the DP8 substrate pocket and dimer interface differ from DPIV and FAP which could be utilised for designing more selective DP8 inhibitors.

Hydrophilic residues surrounding the S1 and S2 pockets contribute to dimerisation and catalysis in human dipeptidyl peptidase 8 (DP8)