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).

 


This family belongs to the Hydrolase Superfamily.
 

References:

Cacace, R., B. Heeman, S. Van Mossevelde, A. De Roeck, J. Hoogmartens, P. De Rijk, H. Gossye, K. De Vos, W. De Coster, M. Strazisar, G. De Baets, J. Schymkowitz, F. Rousseau, N. Geerts, T. De Pooter, K. Peeters, A. Sieben, J.J. Martin, S. Engelborghs, E. Salmon, P. Santens, R. Vandenberghe, P. Cras, P. P De Deyn, J. C van Swieten, C. M van Duijn, J. van der Zee, K. Sleegers, C. Van Broeckhoven, and. (2019). Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability. Acta Neuropathol. [Epub: Ahead of Print]
Cheng, C.S., P.W. Yang, Y. Sun, S.L. Song, and Z. Chen. (2022). Fibroblast activation protein-based theranostics in pancreatic cancer. Front Oncol 12: 969731.
Dougherty, K. and M. Covarrubias. (2006). A dipeptidyl aminopeptidase-like protein remodels gating charge dynamics in Kv4.2 channels. J Gen Physiol 128: 745-753.
Dougherty, K., L. Tu, C. Deutsch, and M. Covarrubias. (2009). The dipeptidyl-aminopeptidase-like protein 6 is an integral voltage sensor-interacting β-subunit of neuronal K(V)4.2 channels. Channels (Austin) 3: 122-128.
Fang, J. and Y. Wei. (2011). Expression, purification and characterization of the Escherichia coli integral membrane protein YajC. Protein Pept Lett 18: 601-608.
Gardel, C., K. Johnson, A. Jacq and J. Beckwith (1990). The secD locus of E. coli codes for two membrane proteins required for protein export. EMBO J. 9: 3209-3216.
Kalaei, Z., R. Manafi-Farid, B. Rashidi, F.K. Kiani, A. Zarei, M. Fathi, and F. Jadidi-Niaragh. (2023). The Prognostic and therapeutic value and clinical implications of fibroblast activation protein-α as a novel biomarker in colorectal cancer. Cell Commun Signal 21: 139.
Kuo, Y.L., J.K. Cheng, W.H. Hou, Y.C. Chang, P.H. Du, J.J. Jian, R.H. Rau, J.H. Yang, C.C. Lien, and M.L. Tsaur. (2017). K+ Channel Modulatory Subunits KChIP and DPP Participate in Kv4-Mediated Mechanical Pain Control. J. Neurosci. 37: 4391-4404.
Lin, L., R.S. Petralia, R. Lake, Y.X. Wang, and D.A. Hoffman. (2020). A novel structure associated with aging is augmented in the DPP6-KO mouse brain. Acta Neuropathol Commun 8: 197.
Maffie, J. and B. Rudy. (2008). Weighing the evidence for a ternary protein complex mediating A-type K+ currents in neurons. J. Physiol. 586: 5609-5623.
Mai, W., Q. Liu, J. Li, M. Zheng, F. Yan, H. Liu, Y. Lei, J. Xu, and J. Xu. (2023). Comprehensive analysis of the oncogenic and immunological role of FAP and identification of the ceRNA network in human cancers. Aging (Albany NY) 15: 3738-3758.
McNicholas, K., T. Chen, and C.A. Abbott. (2009). Dipeptidyl peptidase (DP) 6 and DP10: novel brain proteins implicated in human health and disease. Clin Chem Lab Med 47: 262-267.
Raghav, P.K., K. Kalyanaraman, and D. Kumar. (2021). Human cell receptors: potential drug targets to combat COVID-19. Amino Acids 53: 813-842.
Ren, X., Y. Hayashi, N. Yoshimura, and K. Takimoto. (2005). Transmembrane interaction mediates complex formation between peptidase homologues and Kv4 channels. Mol. Cell Neurosci 29: 320-332.
Reuter, K., R. Slany, F. Ullrich and H. Kersten (1991). Structure and organization of Escherichia coli genes involved in biosynthesis of the deazaguanine derivative queuine, a nutrient factor for eukaryotes. J. Bacteriol. 173: 2256-2264.
Törnroth-Horsefield, S., P. Gourdon, R. Horsefield, L. Brive, N. Yamamoto, H. Mori, A. Snijder, and R. Neutze. (2007). Crystal structure of AcrB in complex with a single transmembrane subunit reveals another twist. Structure. 15: 1663-1673.
Xiong, Y., D. Delic, S. Zeng, X. Chen, C. Chu, A.A. Hasan, B.K. Krämer, T. Klein, L. Yin, and B. Hocher. (2022). Regulation of SARS CoV-2 host factors in the kidney and heart in rats with 5/6 nephrectomy-effects of salt, ARB, DPP4 inhibitor and SGLT2 blocker. BMC Nephrol 23: 117.
Zagha, E., A. Ozaita, S.Y. Chang, M.S. Nadal, U. Lin, M.J. Saganich, T. McCormack, K.O. Akinsanya, S.Y. Qi, and B. Rudy. (2005). DPP10 modulates Kv4-mediated A-type potassium channels. J. Biol. Chem. 280: 18853-18861.
Examples:

TC#NameOrganismal TypeExample
Examples:

TC#NameOrganismal TypeExample
8.A.51.1.1

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).

Animals

 

Dpp6 of Homo sapiens

 
8.A.51.1.2

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

 
8.A.51.1.3

Dipeptide peptidase, DPP8 of 1452 aas and possibly 3 or 4 TMSs.

DPP8 of Trichinella patagoniensis

 
8.A.51.1.4

Peptidase S9B dipeptidylpeptidase IV domain protein of 691 aas

Peptidase S9B of Rhodopirellula sp. SWK7

 
8.A.51.1.5

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

 
8.A.51.1.6

Prolyl endopeptidase, FAP or FAPα; also called melanoma membrane-bound gelatinase and dipeptidyl peptidase  of 760 aas and 2 TMSs, N- and C-terminal.  It plays oncogenic and immunological roles in human cancers (Mai et al. 2023). FAP is a biomarker in colorectal cancer (Kalaei et al. 2023). FAP is a serine protease that has specific endopeptidase activity. It is implicated in diverse cancer-related signaling pathways, contributing to cancer progression, invasion, migration, metastasis, immunosuppression, and resistance to treatment (Cheng et al. 2022).

FAP of Homo sapiens