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

Gustavo Arruda Bezerra,Sofiya Fedosyuk,Elena Dobrovetsky,Alma Seitova,Karl Gruber,Sirano Dhe-Paganon

doi:10.1038/srep08769

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.

Highlights

The voltage-gated potassium channel family (Kv) constitutes the most diverse class of ion channels in the nervous system
The Ca21 binding proteins (KChIPS) and the dipeptidylpeptidase-like proteins (DPPLs) DPP6 and Dipeptidyl peptidase 10 (DPP10) associate with the a-subunits of the Kv4 subfamily to form a ternary complex of approximately 750 kDa containing 12 protein molecules (4 copies of each protein per channel)[6]
Because DPP10 was expressed in SF9 insect cells, we modeled the carbohydrates based on the Asn-b1-GlcNacb1,4-GlcNac-b1,4-Man-a1,3-Man motif, as it is often the final glycan structure found in insects[28]

Summary

Introduction

The voltage-gated potassium channel family (Kv) constitutes the most diverse class of ion channels in the nervous system. Kv4 is a highly conserved subfamily of voltage-gated potassium channels, members of which are expressed in the soma and dendrites of central neurons[3] and modulate A-type potassium currents (Isa). This family of ion channels regulates the propagation of action potential, firing frequency and synaptic integration/plasticity, and has been implicated in neuronal and heart disorders[4]. Pore forming subunits of Kv4 subfamily are embedded in the membrane, with KChIPs assembling at the cytoplasmic side and DPPLs at the extracellular side (Fig. S1)[7] These associated subunits play an important regulatory role by modulating the electrophysiological properties, cell-surface expression and subcellular localization of the channels. The molecular roles of these proteins are unrelated to serine protease catalytic activity

Methods

Results

Conclusion