6b8q

Crystal Structure of the Mg2+/CaM:Kv7.5 (KCNQ5) AB domain complexCrystal Structure of the Mg2+/CaM:Kv7.5 (KCNQ5) AB domain complex

Structural highlights

6b8q is a 8 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:	X-ray diffraction, Resolution 2.6Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

KCNQ5_HUMAN The disease is caused by mutations affecting the gene represented in this entry.

Function

KCNQ5_HUMAN Associates with KCNQ3 to form a potassium channel which contributes to M-type current, a slowly activating and deactivating potassium conductance which plays a critical role in determining the subthreshold electrical excitability of neurons. Therefore, it is important in the regulation of neuronal excitability. May contribute, with other potassium channels, to the molecular diversity of a heterogeneous population of M-channels, varying in kinetic and pharmacological properties, which underlie this physiologically important current. Insensitive to tetraethylammonium, but inhibited by barium, linopirdine and XE991. Activated by niflumic acid and the anticonvulsant retigabine. As the native M-channel, the potassium channel composed of KCNQ3 and KCNQ5 is also suppressed by activation of the muscarinic acetylcholine receptor CHRM1.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Kv7 (KCNQ) voltage-gated potassium channels control excitability in the brain, heart, and ear. Calmodulin (CaM) is crucial for Kv7 function, but how this calcium sensor affects activity has remained unclear. Here, we present X-ray crystallographic analysis of CaM:Kv7.4 and CaM:Kv7.5 AB domain complexes that reveal an Apo/CaM clamp conformation and calcium binding preferences. These structures, combined with small-angle X-ray scattering, biochemical, and functional studies, establish a regulatory mechanism for Kv7 CaM modulation based on a common architecture in which a CaM C-lobe calcium-dependent switch releases a shared Apo/CaM clamp conformation. This C-lobe switch inhibits voltage-dependent activation of Kv7.4 and Kv7.5 but facilitates Kv7.1, demonstrating that mechanism is shared by Kv7 isoforms despite the different directions of CaM modulation. Our findings provide a unified framework for understanding how CaM controls different Kv7 isoforms and highlight the role of membrane proximal domains for controlling voltage-gated channel function. VIDEO ABSTRACT.

A Calmodulin C-Lobe Ca(2+)-Dependent Switch Governs Kv7 Channel Function.,Chang A, Abderemane-Ali F, Hura GL, Rossen ND, Gate RE, Minor DL Jr. Neuron. 2018 Feb 21;97(4):836-852.e6. doi: 10.1016/j.neuron.2018.01.035. Epub, 2018 Feb 8. PMID:29429937^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lerche C, Scherer CR, Seebohm G, Derst C, Wei AD, Busch AE, Steinmeyer K. Molecular cloning and functional expression of KCNQ5, a potassium channel subunit that may contribute to neuronal M-current diversity. J Biol Chem. 2000 Jul 21;275(29):22395-400. doi: 10.1074/jbc.M002378200. PMID:10787416 doi:http://dx.doi.org/10.1074/jbc.M002378200
↑ Wickenden AD, Zou A, Wagoner PK, Jegla T. Characterization of KCNQ5/Q3 potassium channels expressed in mammalian cells. Br J Pharmacol. 2001 Jan;132(2):381-4. PMID:11159685 doi:http://dx.doi.org/10.1038/sj.bjp.0703861
↑ Lehman A, Thouta S, Mancini GMS, Naidu S, van Slegtenhorst M, McWalter K, Person R, Mwenifumbo J, Salvarinova R, Guella I, McKenzie MB, Datta A, Connolly MB, Kalkhoran SM, Poburko D, Friedman JM, Farrer MJ, Demos M, Desai S, Claydon T. Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy. Am J Hum Genet. 2017 Jul 6;101(1):65-74. doi: 10.1016/j.ajhg.2017.05.016. Epub, 2017 Jun 29. PMID:28669405 doi:http://dx.doi.org/10.1016/j.ajhg.2017.05.016
↑ Chang A, Abderemane-Ali F, Hura GL, Rossen ND, Gate RE, Minor DL Jr.. A Calmodulin C-Lobe Ca(2+)-Dependent Switch Governs Kv7 Channel Function. Neuron. 2018 Feb 21;97(4):836-852.e6. doi: 10.1016/j.neuron.2018.01.035. Epub, 2018 Feb 8. PMID:29429937 doi:http://dx.doi.org/10.1016/j.neuron.2018.01.035

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Lerche C, Scherer CR, Seebohm G, Derst C, Wei AD, Busch AE, Steinmeyer K. Molecular cloning and functional expression of KCNQ5, a potassium channel subunit that may contribute to neuronal M-current diversity. J Biol Chem. 2000 Jul 21;275(29):22395-400. doi: 10.1074/jbc.M002378200. PMID:10787416 doi:http://dx.doi.org/10.1074/jbc.M002378200

[2] Wickenden AD, Zou A, Wagoner PK, Jegla T. Characterization of KCNQ5/Q3 potassium channels expressed in mammalian cells. Br J Pharmacol. 2001 Jan;132(2):381-4. PMID:11159685 doi:http://dx.doi.org/10.1038/sj.bjp.0703861

[3] Lehman A, Thouta S, Mancini GMS, Naidu S, van Slegtenhorst M, McWalter K, Person R, Mwenifumbo J, Salvarinova R, Guella I, McKenzie MB, Datta A, Connolly MB, Kalkhoran SM, Poburko D, Friedman JM, Farrer MJ, Demos M, Desai S, Claydon T. Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy. Am J Hum Genet. 2017 Jul 6;101(1):65-74. doi: 10.1016/j.ajhg.2017.05.016. Epub, 2017 Jun 29. PMID:28669405 doi:http://dx.doi.org/10.1016/j.ajhg.2017.05.016

[4] Chang A, Abderemane-Ali F, Hura GL, Rossen ND, Gate RE, Minor DL Jr.. A Calmodulin C-Lobe Ca(2+)-Dependent Switch Governs Kv7 Channel Function. Neuron. 2018 Feb 21;97(4):836-852.e6. doi: 10.1016/j.neuron.2018.01.035. Epub, 2018 Feb 8. PMID:29429937 doi:http://dx.doi.org/10.1016/j.neuron.2018.01.035

[1]

[2]

[3]

[4]