8.A.51 The Dipeptidyl-aminopeptidase-like Protein 6 beta subunit of Kv4 channels (DPP6) Family
Auxiliary beta-subunits dictate the physiological properties of voltage-gated K+ (KV) channels in excitable tissues. The dipeptidyl-aminopeptidase-like protein 6 (DPP6) is a specific β-subunit of neuronal KV4 channels, which may promote gating through interactions between the single transmembrane segment of DPP6 and the channel's voltage sensing domain (VSD) (Maffie and Rudy 2008). A combination of gating current measurements and protein biochemistry (in-vitro translation and co- immunoprecipitations) revealed preferential physical interaction between the isolated KV4.2-VSD and DPP6 (Dougherty et al. 2009). Significantly weaker interactions were detected between DPP6 and KV1.3 channels or the KV4.2 pore domain (McNicholas et al. 2009). More efficient gating charge movement resulting from a direct interaction between DPP6 and the KV4.2-VSD is unique among the known actions of KV channel beta-subunits. Thus. the modular VSD of a KV channel can be directly regulated by transmembrane protein-protein interactions involving an extrinsic β-subunit. Understanding these interactions may shed light on the pathophysiology of recently identified human disorders associated with mutations affecting the dpp6 gene. Loss of DPP6 influences neuronal excitability and promotes neurodegnerative dementia (Cacace et al. 2019).
The dipeptidyl aminopeptidase-like protein 6, β-subunit, Dpp6, DPPX-S or DPLP (865 aas) of the Kv4.2 K+ channel (TC# 1.A.1.2.5; Dougherty et al. 2009). DPPX-S destabilizes resting and intermediate states in the voltage-dependent activation pathway, which promotes the outward gating charge movement (Dougherty and Covarrubias 2006). It is an auxiliary subunit of A-type voltage-gated K+ channels, and this single transmembrane protein impacts neuronal and synaptic development (Lin et al. 2020).
Dpp6 of Homo sapiens
The inactive dipeptidyl peptidase or prolyl oligopeptidase, DPP10 (DPPY, DPRP-3, DPL2, DPPIV or DPR3) is of 798 aas with 1 N-terminal TMS. It preferentially binds to Kv4 channel proteins to increase current density and alter channel gating (Ren et al. 2005; Zagha et al. 2005). DPP10 also forms complexes with itself and with DPPX in the absence of Kv4 channels. DPP10 mRNA is abundantly expressed in nodose and dorsal root ganglia, suggesting that DPP10 participates in controlling airway reactivity and mechanosensation. The region from the N-terminus to the end of the TMS mediates its association with the channel, whereas the S1-S2 portion of the channel is sufficient for complex formation. This N-terminal portion of DPP10 also confers all the gating effects produced by the peptidase homologue (Ren et al. 2005). DPP10 has an N-terminal DPPIV_N domain and a C-terminal abhydrolase domain. It is an inactivating modulator of Kv4 channels and the Kv1.4 channel (Kuo et al. 2017). DPP10 and KChIP2b (Q9NS61; TC# 8.a.82.2.4) both modulate Kv4.3 inactivation, but their primary effects are on different inactivation states (Kuo et al. 2017).
DPP10 of Homo sapiens
Dipeptide peptidase, DPP8 of 1452 aas and possibly 3 or 4 TMSs.
DPP8 of Trichinella patagoniensis
Peptidase S9B dipeptidylpeptidase IV domain protein of 691 aas
Peptidase S9B of Rhodopirellula sp. SWK7
Dipeptide peptidase 4, DPP4, of 766 aas and 1 or 2 TMSs, one at the N-terminus, and possibly a second near the C-terminus. It has been consdered to be a potential drug target for combating SARS CoV2 (Raghav et al. 2021). There is no upregulation regarding host factors potentially promoting SARS-CoV-2 virus entry into host cells when the SGLT2-blocker empagliflozin, telmisartan and the DPP4-inhibitor blocker, linagliptin, are used (Xiong et al. 2022).
DPP4 of Homo sapiens