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

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.

Kv4.2 and Accessory Dipeptidyl Peptidase-like Protein 10 (DPP10) Subunit Preferentially Form a 4:2 (Kv4.2:DPP10) Channel Complex

“…It has also been reported that the extracellular domain-less DPP6 mutants (DPP6-D-Extra) can bind to and modulate Kv4.2 channels (41). On the other hand, the crystal structure demonstrates that the extracellular domain of DPP6/10 forms a dimeric structure (26,48). DPP4, which is a membrane-bound enzyme and does not modulate Kv4, shows catalytic activity when it forms a dimer (63).…”

“…Because the amino acid identity of the transmembrane domain between DPP6 and DPP10 is high (91%) and the transmembrane domain of DPP10 is important for the binding to Kv4.2, DPP6 may form a heteromultimeric complex with DPP10 (47,48). The combination of Kv4, KChIP, and DPP6/10 in the complex would give rise to further diversity of the biophysical properties and may dynamically regulate cell excitability by a complicated stoichiometry.…”

“…The extracellular domain of DPP6/10 forms a dimeric structure according to the crystal structure (26,48) and our subunit counting experiment (Fig. 3).…”

“…The crystal structure of the extracellular domain shows that DPP6 forms a dimeric structure (26). The recently published crystal structure of the extracellular domain of DPP10 shows a similar dimeric structure (48). To examine whether the full-length DPP10 actually exists as a dimer in the membrane, we constructed mEGFP-tagged DPP10 (mEGFP-DPP10) in which mEGFP was fused to the intracellular N terminus of DPP10 (Fig.…”

“…However, it remains uncertain how many DPP subunits can bind to a tetrameric Kv4 channel. Although there is no available crystal structure for the Kv4-DPP complex, a crystal structure of the extracellular domains of DPP6/10 has been determined, and it is suggested that DPP6 and DPP10 exist as a dimer in the plasma membrane (26,48). This implies the possibility that Kv4 and DPP preferentially form a 4:2 (Kv4:DPP) channel.…”