Structure of human dipeptidyl peptidase 10 (DPPY): a modulator of neuronal Kv4 channels.
The voltage-gated potassium channel family (Kv) constitutes the most diverse class of ion channels in the nervous system. Dipeptidyl peptidase 10 (DPP10) is an inactive peptidase that modulates the electrophysiological properties, cell-surface expression and subcellular localization of voltage-gated potassium channels. As a consequence, DPP10 malfunctioning is associated with neurodegenerative conditions like Alzheimer and fronto-temporal dementia, making this protein an attractive drug target. In this work, we report the crystal structure of DPP10 and compare it to that of DPP6 and DPP4. DPP10 belongs to the S9B serine protease subfamily and contains two domains with two distinct folds: a β-propeller and a classical α/β-hydrolase fold. The catalytic serine, however, is replaced by a glycine, rendering the protein enzymatically inactive. Difference in the entrance channels to the active sites between DPP10 and DPP4 provide an additional rationale for the lack of activity. We also characterize the DPP10 dimer interface focusing on the alternative approach for designing drugs able to target protein-protein interactions.
Institute of Molecular Biosciences, University of Graz, Humboldtstraße 50/3, A-8010 Graz, Austria.
Gustavo Arruda
GA
Bezerra
Department of Physiology and Structural Genomics Consortium, University of Toronto, MaRS Centre, South Tower, 101 College St., Suite 700, Toronto, ON, M5G 1L7, Canada.
Elena
E
Dobrovetsky
Department of Physiology and Structural Genomics Consortium, University of Toronto, MaRS Centre, South Tower, 101 College St., Suite 700, Toronto, ON, M5G 1L7, Canada.
Alma
A
Seitova
Max F. Perutz Laboratories, Medical University of Vienna, Dr. Bohr-Gasse 9/3, A-1030 Vienna, Austria.
Sofiya
S
Fedosyuk
Department of Physiology and Structural Genomics Consortium, University of Toronto, MaRS Centre, South Tower, 101 College St., Suite 700, Toronto, ON, M5G 1L7, Canada.
Sirano
S
Dhe-Paganon
Institute of Molecular Biosciences, University of Graz, Humboldtstraße 50/3, A-8010 Graz, Austria.
Karl
K
Gruber
D020134:Catalytic Domain; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000737:chemistry* / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D008958:Models, Molecular; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D051672:Shal Potassium Channels / Q000378:metabolism
D051672:Shal Potassium Channels; C476879:DPP10 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases