Structure of human dipeptidyl peptidase 10 (DPPY): a modulator of neuronal Kv4 channels

Scientific Reports
Gustavo Arruda BezerraKarl Gruber

Abstract

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.

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Citations

Sep 24, 2016·Respiratory Research·Fatemeh MoheimaniDarryl A Knight
May 21, 2016·Scientific Reports·Yohei ShiinaKoichi Takimoto
Oct 13, 2018·Protein Science : a Publication of the Protein Society·Polytimi S DimitriouKonstantin Denessiouk
Sep 26, 2019·Current Protein & Peptide Science·Anna J Kiss-SzemánDóra K Menyhárd
Aug 24, 2018·Molecular Medicine·Antonela MatanaTatijana Zemunik
Feb 1, 2020·Bioinformatics·Gabriel E HoffmanPanos Roussos
Aug 12, 2019·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Shreyasi Gupta, Utpal Sen
May 21, 2020·Biochimica Et Biophysica Acta. General Subjects·Yakov E DunaevskyElena N Elpidina
Jun 3, 2021·Acta Crystallographica. Section D, Structural Biology·Leona ŠvecováJan Dohnálek

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Datasets Mentioned

BETA
AAH30832.1

Methods Mentioned

BETA
glycosylation
PISA
size-exclusion chromatography

Software Mentioned

BALBES
PyMOL
MOLPROBITY
CCP4
MOSFLM
Blast search
Caver
SCALA
COOT
PHENIX

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