title: DPP6 domains responsible for its localization and function.
abstract: Dipeptidyl peptidase-like protein 6 (DPP6) is an auxiliary subunit of the Kv4 family of voltage-gated K(+) channels known to enhance channel surface expression and potently accelerate their kinetics. DPP6 is a single transmembrane protein, which is structurally remarkable for its large extracellular domain. Included in this domain is a cysteine-rich motif, the function of which is unknown. Here we show that this cysteine-rich domain of DPP6 is required for its export from the ER and expression on the cell surface. Disulfide bridges formed at C349/C356 and C465/C468 of the cysteine-rich domain are necessary for the enhancement of Kv4.2 channel surface expression but not its interaction with Kv4.2 subunits. The short intracellular N-terminal and transmembrane domains of DPP6 associates with and accelerates the recovery from inactivation of Kv4.2, but the entire extracellular domain is necessary to enhance Kv4.2 surface expression and stabilization. Our findings show that the cysteine-rich domain of DPP6 plays an important role in protein folding of DPP6 that is required for transport of DPP6/Kv4.2 complexes out of the ER.
authors.affiliation: Molecular Neurophysiology and Biophysics Section, Program in Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892. Electronic address: linl2@mail.nih.gov.
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.affiliation: Molecular Neurophysiology and Biophysics Section, Program in Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Long
authors.affiliation: Molecular Neurophysiology and Biophysics Section, Program in Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Hatch
authors.affiliation: Molecular Neurophysiology and Biophysics Section, Program in Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Dax A
authors.initials: DA
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D019921:Biotinylation; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D003545:Cysteine / Q000737:chemistry; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000737:chemistry* / Q000502:physiology*; D004220:Disulfides / Q000737:chemistry; D004594:Electrophysiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008564:Membrane Potentials; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D015221:Potassium Channels / Q000737:chemistry* / Q000502:physiology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051672:Shal Potassium Channels / Q000737:chemistry
chemical_list: D004220:Disulfides; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D051672:Shal Potassium Channels; C503535:DPP6 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D003545:Cysteine
keywords: Endoplasmic Reticulum (ER); Intracellular Trafficking; Membrane Trafficking; Neuron; Neuronal Excitability; Potassium Channel; dpp6; kv4.2