DPP10

DPP10 is an N-glycosylated type II transmembrane protein that functions as an auxiliary subunit of voltage-gated potassium channels, controlling the trafficking and gating of Kv4 channels that generate neuronal A-type currents (PMID:15671030, PMID:15454437). Although it adopts the β-propeller plus α/β-hydrolase architecture of the S9B dipeptidyl peptidase family, its catalytic serine is replaced by glycine, and mutagenesis aimed at restoring the active site fails to confer enzymatic activity, establishing DPP10 as a catalytically dead pseudo-peptidase (PMID:16290253, PMID:25740212). DPP10 physically associates with Kv4.2 and Kv4.3, promotes their surface expression, and accelerates inactivation and recovery from inactivation while introducing hyperpolarizing shifts in voltage dependence; these gating effects are conferred by its transmembrane and intracellular regions rather than its extracellular ectodomain (PMID:15671030, PMID:15454437, PMID:16738002). Together with KChIP subunits, DPP10 assembles into ternary Kv4/KChIP/DPP10 complexes that reconstitute current waveforms and recovery kinetics matching native neuronal ISA, and such complexes are co-localized in defined neuronal populations in vivo (PMID:16123112, PMID:25355692). Channel modulation is stoichiometry-dependent, with DPP10 preferentially forming a 4:2 (Kv4:DPP10) complex, and depends critically on N-linked glycosylation, where site-specific glycans (notably N257) drive DPP10 surface sorting, dimerization, and functional interaction with the channel (PMID:22387313, PMID:26209633). Beyond Kv4, DPP10 physically interacts with cardiac Nav1.5 channels in human ventricle and modifies sodium current density and gating (PMID:30638748). DPP10 protein is also redistributed to neurofibrillary tangles and dystrophic neurites in Alzheimer's disease brain (PMID:25025038).

1. 2004 High

   Established that DPP10 is a functional Kv4 channel partner, not merely a co-expressed protein, by showing it binds Kv4.2 and remodels its surface current and gating.

   Evidence Co-immunoprecipitation and two-electrode voltage-clamp in Xenopus oocytes with N-terminal truncation mapping

   PMID:15454437

   Open questions at the time

   • Performed in heterologous oocytes only
   • Did not address whether native brain complexes exist
   • Stoichiometry of the complex unresolved
2. 2005 High

   Confirmed the Kv4.2-DPP10 interaction occurs natively in brain and localized the modulatory determinant to the transmembrane/intracellular domains, defining how DPP10 sculpts A-type currents.

   Evidence Co-immunoprecipitation from rat brain membranes, heterologous electrophysiology, domain-swap chimeras, in situ hybridization

   PMID:15671030

   Open questions at the time

   • Did not establish three-way complex with KChIPs
   • Mechanism of gating modulation at structural level unknown
3. 2005 High

   Demonstrated that DPP10 is enzymatically dead despite its peptidase fold, reframing it as a non-catalytic accessory subunit rather than an active dipeptidyl peptidase.

   Evidence Site-directed mutagenesis of the catalytic motif with enzyme activity assays, PNGase F deglycosylation, cell-surface analysis

   PMID:16290253

   Open questions at the time

   • Why active-site reconstitution failed to restore activity not structurally explained at the time
   • Soluble vs transmembrane form roles unclear
4. 2005 High

   Showed that Kv4/KChIP/DPP10 form a ternary macromolecular complex whose gating reconstitutes native neuronal ISA, defining the physiological channel assembly.

   Evidence Co-immunoprecipitation from rat brain and heterologous cells with electrophysiology in oocytes and CHO cells

   PMID:16123112

   Open questions at the time

   • Subunit stoichiometry not quantified
   • Spatial distribution in defined neuron types not yet shown
5. 2006 Medium

   Extended DPP10 modulation beyond Kv4 to Kv1.4 and mapped the minimal modulatory unit to the transmembrane plus a short cytoplasmic segment, distinguishing DPP10's action from KChIP on channel inactivation states.

   Evidence Heterologous patch-clamp co-expression with truncation mutant analysis

   PMID:16738002 PMID:16899223

   Open questions at the time

   • Conflicting conclusions on N-terminal requirement across studies
   • Single expression system
6. 2007 High

   Showed splice variants tune the gating phenotype of the ternary complex, providing a mechanism for regional diversity of A-type currents.

   Evidence Electrophysiology of DPP10 isoforms in oocytes and CHO cells with qRT-PCR and in situ hybridization

   PMID:17475505

   Open questions at the time

   • Functional consequence of isoform distribution in vivo untested
   • Structural basis of isoform-specific kinetics unknown
7. 2012 High

   Defined N-linked glycosylation, particularly at N257, as required for DPP10 trafficking, dimerization, and functional channel modulation, linking post-translational modification to assembly.

   Evidence Site-directed N→Q mutagenesis with flow cytometry, co-IP, and electrophysiology; complemented by tunicamycin/neuraminidase disruption in CHO cells and human atrial myocytes

   PMID:20354865 PMID:22387313

   Open questions at the time

   • How glycosylation mechanistically enables dimerization not resolved
   • In vivo relevance of individual glycosites untested
8. 2014 Medium

   Localized DPP10 to specific neuronal populations alongside Kv4 and KChIP subunits, and documented its aberrant redistribution to tau pathology in Alzheimer's disease.

   Evidence Immunohistochemistry and triple immunofluorescence co-localization in rat and human brain, Western blot

   PMID:25025038 PMID:25355692

   Open questions at the time

   • Causal role of DPP10 in AD pathology not established
   • Functional consequence of fragment accumulation unknown
9. 2015 High

   Provided the structural basis for enzymatic inactivity and quantified the preferred 4:2 Kv4:DPP10 stoichiometry, explaining how the extracellular dimer constrains complex assembly and modulation.

   Evidence X-ray crystallography of human DPP10; single-molecule subunit counting plus variable-ratio electrophysiology in oocytes

   PMID:25740212 PMID:26209633

   Open questions at the time

   • No structure of the assembled Kv4/DPP10 complex
   • How transmembrane/intracellular domains transmit gating effects not captured by ectodomain structure
10. 2016 Medium

    Showed the Drosophila ortholog is both a Kv4 ancillary subunit and an active dipeptidyl peptidase, establishing that the ancestral protein was bifunctional and enzymatic activity was lost in mammalian DPP10.

    Evidence Co-IP, electrophysiology, and fluorescent-substrate enzymatic assay on the ortholog

    PMID:27198182

    Open questions at the time

    • Ortholog assay does not address human DPP10 physiology
    • Single lab, two methods
11. 2019 Medium

    Identified cardiac Nav1.5 as a DPP10 partner, broadening its role beyond potassium channels into sodium current regulation in the heart.

    Evidence Co-immunoprecipitation from human ventricular tissue and adenoviral overexpression with patch-clamp in rat cardiomyocytes

    PMID:30638748

    Open questions at the time

    • Single lab
    • Physiological/arrhythmic consequence in vivo not established
    • Domain requirements for Nav1.5 modulation unmapped

• How DPP10's transmembrane and intracellular domains physically couple to and reshape channel gating, and whether its multiple channel partnerships (Kv4, Kv1.4, Nav1.5) operate through a shared mechanism, remain unresolved.
• No structure of an assembled channel-DPP10 complex
• Shared vs distinct modulatory mechanism across channel families unknown
• Physiological consequences of loss in mammals uncharacterized