| Structural highlights
Disease
[KCNQ4_HUMAN] Defects in KCNQ4 are the cause of deafness autosomal dominant type 2A (DFNA2A) [MIM:600101]. DFNA2A is a form of sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information.[1] [2] [3] [4] [5] [CALM1_HUMAN] The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of CPVT4. The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of LQT14.
Function
[KCNQ4_HUMAN] Probably important in the regulation of neuronal excitability. May underlie a potassium current involved in regulating the excitability of sensory cells of the cochlea. KCNQ4 channels are blocked by linopirdin, XE991 and bepridil, whereas clofilium is without significant effect. Muscarinic agonist oxotremorine-M strongly suppress KCNQ4 current in CHO cells in which cloned KCNQ4 channels were coexpressed with M1 muscarinic receptors.[6] [CALM1_HUMAN] Calmodulin mediates the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding. Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases and phosphatases. Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis (PubMed:16760425). Mediates calcium-dependent inactivation of CACNA1C (PubMed:26969752). Positively regulates calcium-activated potassium channel activity of KCNN2 (PubMed:27165696).[7] [8] [9] [10]
Publication Abstract from PubMed
Calmodulin (CaM) conveys intracellular Ca(2+) signals to KCNQ (Kv7, "M-type") K(+) channels and many other ion channels. Whether this "calmodulation" involves a dramatic structural rearrangement or only slight perturbations of the CaM-KCNQ complex is as yet unclear. A consensus structural model of conformational shifts occurring between low-nM to physiologically high intracellular [Ca(2+)] is still under debate. Here, we used various techniques of biophysical chemical analyses to investigate the interactions between CaM and synthetic peptides corresponding to the A and B domains of the KCNQ4 subtype. We found that in the absence of CaM, the peptides are disordered, whereas Ca(2+)/CaM imposed helical structure on both KCNQ A and B domains. Isothermal titration calorimetry revealed that Ca(2+)/CaM has higher affinity for the B domain than for the A domain of KCNQ2-4 and much higher affinity for the B domain when prebound with the A domain. X-ray crystallography confirmed these discrete peptides spontaneously bind Ca(2+)/CaM, similar to previous reports of CaM binding KCNQ-AB domains that are linked together. Microscale thermophoresis and HSQC-NMR indicated the C-lobe of Ca(2+)-free CaM to interact with the KCNQ4 B domain (Kd ~10-20 microM), with increasing Ca(2+) molar ratios shifting the CaM-B domain interactions via only the CaM C-lobe to also include the N-lobe. Our findings suggest that in response to increased Ca(2+), CaM undergoes lobe-switching that imposes a dramatic mutually induced conformational fit to both the proximal C-terminus of KCNQ4 channels and CaM, likely underlying Ca(2+)-dependent regulation of KCNQ gating.
A mutually-induced conformational fit underlies Ca(2+)-directed interactions between calmodulin and the proximal C terminus of KCNQ4 K(+) channels.,Archer CR, Enslow BT, Taylor AB, De la Rosa V, Bhattacharya A, Shapiro MS J Biol Chem. 2019 Feb 26. pii: RA118.006857. doi: 10.1074/jbc.RA118.006857. PMID:30808708[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kubisch C, Schroeder BC, Friedrich T, Lutjohann B, El-Amraoui A, Marlin S, Petit C, Jentsch TJ. KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell. 1999 Feb 5;96(3):437-46. PMID:10025409
- ↑ Coucke PJ, Van Hauwe P, Kelley PM, Kunst H, Schatteman I, Van Velzen D, Meyers J, Ensink RJ, Verstreken M, Declau F, Marres H, Kastury K, Bhasin S, McGuirt WT, Smith RJ, Cremers CW, Van de Heyning P, Willems PJ, Smith SD, Van Camp G. Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. Hum Mol Genet. 1999 Jul;8(7):1321-8. PMID:10369879
- ↑ Talebizadeh Z, Kelley PM, Askew JW, Beisel KW, Smith SD. Novel mutation in the KCNQ4 gene in a large kindred with dominant progressive hearing loss. Hum Mutat. 1999;14(6):493-501. PMID:10571947 doi:<493::AID-HUMU8>3.0.CO;2-P 10.1002/(SICI)1098-1004(199912)14:6<493::AID-HUMU8>3.0.CO;2-P
- ↑ Van Hauwe P, Coucke PJ, Ensink RJ, Huygen P, Cremers CW, Van Camp G. Mutations in the KCNQ4 K+ channel gene, responsible for autosomal dominant hearing loss, cluster in the channel pore region. Am J Med Genet. 2000 Jul 31;93(3):184-7. PMID:10925378
- ↑ Arnett J, Emery SB, Kim TB, Boerst AK, Lee K, Leal SM, Lesperance MM. Autosomal dominant progressive sensorineural hearing loss due to a novel mutation in the KCNQ4 gene. Arch Otolaryngol Head Neck Surg. 2011 Jan;137(1):54-9. doi:, 10.1001/archoto.2010.234. PMID:21242547 doi:10.1001/archoto.2010.234
- ↑ Sogaard R, Ljungstrom T, Pedersen KA, Olesen SP, Jensen BS. KCNQ4 channels expressed in mammalian cells: functional characteristics and pharmacology. Am J Physiol Cell Physiol. 2001 Apr;280(4):C859-66. PMID:11245603
- ↑ Tsang WY, Spektor A, Luciano DJ, Indjeian VB, Chen Z, Salisbury JL, Sanchez I, Dynlacht BD. CP110 cooperates with two calcium-binding proteins to regulate cytokinesis and genome stability. Mol Biol Cell. 2006 Aug;17(8):3423-34. Epub 2006 Jun 7. PMID:16760425 doi:10.1091/mbc.E06-04-0371
- ↑ Reichow SL, Clemens DM, Freites JA, Nemeth-Cahalan KL, Heyden M, Tobias DJ, Hall JE, Gonen T. Allosteric mechanism of water-channel gating by Ca-calmodulin. Nat Struct Mol Biol. 2013 Jul 28. doi: 10.1038/nsmb.2630. PMID:23893133 doi:10.1038/nsmb.2630
- ↑ Boczek NJ, Gomez-Hurtado N, Ye D, Calvert ML, Tester DJ, Kryshtal D, Hwang HS, Johnson CN, Chazin WJ, Loporcaro CG, Shah M, Papez AL, Lau YR, Kanter R, Knollmann BC, Ackerman MJ. Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome-Associated Calmodulin Missense Variant, E141G. Circ Cardiovasc Genet. 2016 Apr;9(2):136-146. doi:, 10.1161/CIRCGENETICS.115.001323. Epub 2016 Mar 11. PMID:26969752 doi:http://dx.doi.org/10.1161/CIRCGENETICS.115.001323
- ↑ Yu CC, Ko JS, Ai T, Tsai WC, Chen Z, Rubart M, Vatta M, Everett TH 4th, George AL Jr, Chen PS. Arrhythmogenic calmodulin mutations impede activation of small-conductance calcium-activated potassium current. Heart Rhythm. 2016 Aug;13(8):1716-23. doi: 10.1016/j.hrthm.2016.05.009. Epub 2016, May 7. PMID:27165696 doi:http://dx.doi.org/10.1016/j.hrthm.2016.05.009
- ↑ Archer CR, Enslow BT, Taylor AB, De la Rosa V, Bhattacharya A, Shapiro MS. A mutually-induced conformational fit underlies Ca(2+)-directed interactions between calmodulin and the proximal C terminus of KCNQ4 K(+) channels. J Biol Chem. 2019 Feb 26. pii: RA118.006857. doi: 10.1074/jbc.RA118.006857. PMID:30808708 doi:http://dx.doi.org/10.1074/jbc.RA118.006857
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