7ukd

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Human Kv4.2-KChIP2 channel complex in an inactivated state, class 2, transmembrane regionHuman Kv4.2-KChIP2 channel complex in an inactivated state, class 2, transmembrane region

Structural highlights

7ukd is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 2.88Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

KCND2_HUMAN KNCD2 mutations have been found in a family with autism and epilepsy and may play a role in disease pathogenesis. Autism is a complex multifactorial, pervasive developmental disorder characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities by 3 years of age. Epilepsy is characterized by paroxysmal transient disturbances of the electrical activity of the brain that may be manifested as episodic impairment or loss of consciousness, abnormal motor phenomena, psychic or sensory disturbances, or perturbation of the autonomic nervous system.[1] A KCND2 mutation leading to the production of a C-terminally truncated protein has been identified in a patient with epilepsy. Epilepsy is characterized by paroxysmal transient disturbances of the electrical activity of the brain that may be manifested as episodic impairment or loss of consciousness, abnormal motor phenomena, psychic or sensory disturbances, or perturbation of the autonomic nervous system.[2]

Function

KCND2_HUMAN Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain. Mediates the major part of the dendritic A-type current I(SA) in brain neurons (By similarity). This current is activated at membrane potentials that are below the threshold for action potentials. It regulates neuronal excitability, prolongs the latency before the first spike in a series of action potentials, regulates the frequency of repetitive action potential firing, shortens the duration of action potentials and regulates the back-propagation of action potentials from the neuronal cell body to the dendrites. Contributes to the regulation of the circadian rhythm of action potential firing in suprachiasmatic nucleus neurons, which regulates the circadian rhythm of locomotor activity (By similarity). Functions downstream of the metabotropic glutamate receptor GRM5 and plays a role in neuronal excitability and in nociception mediated by activation of GRM5 (By similarity). Mediates the transient outward current I(to) in rodent heart left ventricle apex cells, but not in human heart, where this current is mediated by another family member. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient (PubMed:10551270, PubMed:15454437, PubMed:14695263, PubMed:14623880, PubMed:14980201, PubMed:16934482, PubMed:24811166, PubMed:24501278). The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:11507158). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCND2 and KCND3; channel properties depend on the type of pore-forming alpha subunits that are part of the channel. In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes. Interaction with specific isoforms of the regulatory subunits KCNIP1, KCNIP2, KCNIP3 or KCNIP4 strongly increases expression at the cell surface and thereby increases channel activity; it modulates the kinetics of channel activation and inactivation, shifts the threshold for channel activation to more negative voltage values, shifts the threshold for inactivation to less negative voltages and accelerates recovery after inactivation (PubMed:15454437, PubMed:14623880, PubMed:14980201, PubMed:19171772, PubMed:24501278, PubMed:24811166). Likewise, interaction with DPP6 or DPP10 promotes expression at the cell membrane and regulates both channel characteristics and activity (By similarity).[UniProtKB:Q63881][UniProtKB:Q9Z0V2][3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]

See Also

References

  1. Lee H, Lin MC, Kornblum HI, Papazian DM, Nelson SF. Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation. Hum Mol Genet. 2014 Jul 1;23(13):3481-9. doi: 10.1093/hmg/ddu056. Epub 2014 Feb, 5. PMID:24501278 doi:http://dx.doi.org/10.1093/hmg/ddu056
  2. Singh B, Ogiwara I, Kaneda M, Tokonami N, Mazaki E, Baba K, Matsuda K, Inoue Y, Yamakawa K. A Kv4.2 truncation mutation in a patient with temporal lobe epilepsy. Neurobiol Dis. 2006 Nov;24(2):245-53. doi: 10.1016/j.nbd.2006.07.001. Epub 2006, Aug 24. PMID:16934482 doi:http://dx.doi.org/10.1016/j.nbd.2006.07.001
  3. Zhu XR, Wulf A, Schwarz M, Isbrandt D, Pongs O. Characterization of human Kv4.2 mediating a rapidly-inactivating transient voltage-sensitive K+ current. Recept Channels. 1999;6(5):387-400. PMID:10551270
  4. Isbrandt D, Leicher T, Waldschutz R, Zhu X, Luhmann U, Michel U, Sauter K, Pongs O. Gene structures and expression profiles of three human KCND (Kv4) potassium channels mediating A-type currents I(TO) and I(SA). Genomics. 2000 Mar 1;64(2):144-54. PMID:10729221 doi:http://dx.doi.org/10.1006/geno.2000.6117
  5. Bahring R, Boland LM, Varghese A, Gebauer M, Pongs O. Kinetic analysis of open- and closed-state inactivation transitions in human Kv4.2 A-type potassium channels. J Physiol. 2001 Aug 15;535(Pt 1):65-81. doi: 10.1111/j.1469-7793.2001.00065.x. PMID:11507158 doi:http://dx.doi.org/10.1111/j.1469-7793.2001.00065.x
  6. Kim LA, Furst J, Butler MH, Xu S, Grigorieff N, Goldstein SA. Ito channels are octomeric complexes with four subunits of each Kv4.2 and K+ channel-interacting protein 2. J Biol Chem. 2004 Feb 13;279(7):5549-54. doi: 10.1074/jbc.M311332200. Epub 2003, Nov 17. PMID:14623880 doi:http://dx.doi.org/10.1074/jbc.M311332200
  7. Gebauer M, Isbrandt D, Sauter K, Callsen B, Nolting A, Pongs O, Bahring R. N-type inactivation features of Kv4.2 channel gating. Biophys J. 2004 Jan;86(1 Pt 1):210-23. doi: 10.1016/S0006-3495(04)74097-7. PMID:14695263 doi:http://dx.doi.org/10.1016/S0006-3495(04)74097-7
  8. Kim LA, Furst J, Gutierrez D, Butler MH, Xu S, Goldstein SA, Grigorieff N. Three-dimensional structure of I(to); Kv4.2-KChIP2 ion channels by electron microscopy at 21 Angstrom resolution. Neuron. 2004 Feb 19;41(4):513-9. doi: 10.1016/s0896-6273(04)00050-9. PMID:14980201 doi:http://dx.doi.org/10.1016/s0896-6273(04)00050-9
  9. Jerng HH, Qian Y, Pfaffinger PJ. Modulation of Kv4.2 channel expression and gating by dipeptidyl peptidase 10 (DPP10). Biophys J. 2004 Oct;87(4):2380-96. PMID:15454437 doi:http://dx.doi.org/10.1529/biophysj.104.042358
  10. Singh B, Ogiwara I, Kaneda M, Tokonami N, Mazaki E, Baba K, Matsuda K, Inoue Y, Yamakawa K. A Kv4.2 truncation mutation in a patient with temporal lobe epilepsy. Neurobiol Dis. 2006 Nov;24(2):245-53. doi: 10.1016/j.nbd.2006.07.001. Epub 2006, Aug 24. PMID:16934482 doi:http://dx.doi.org/10.1016/j.nbd.2006.07.001
  11. Barghaan J, Bahring R. Dynamic coupling of voltage sensor and gate involved in closed-state inactivation of kv4.2 channels. J Gen Physiol. 2009 Feb;133(2):205-24. doi: 10.1085/jgp.200810073. PMID:19171772 doi:http://dx.doi.org/10.1085/jgp.200810073
  12. Lee H, Lin MC, Kornblum HI, Papazian DM, Nelson SF. Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation. Hum Mol Genet. 2014 Jul 1;23(13):3481-9. doi: 10.1093/hmg/ddu056. Epub 2014 Feb, 5. PMID:24501278 doi:http://dx.doi.org/10.1093/hmg/ddu056
  13. Kitazawa M, Kubo Y, Nakajo K. The stoichiometry and biophysical properties of the Kv4 potassium channel complex with K+ channel-interacting protein (KChIP) subunits are variable, depending on the relative expression level. J Biol Chem. 2014 Jun 20;289(25):17597-609. doi: 10.1074/jbc.M114.563452. Epub, 2014 May 8. PMID:24811166 doi:http://dx.doi.org/10.1074/jbc.M114.563452

7ukd, resolution 2.88Å

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