| Structural highlights
6mc9 is a 2 chain structure with sequence from Buffalo rat and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | |
| Gene: | SCN4A (HUMAN), Calm1, Calm, Cam, Cam1, CaMI (Buffalo rat) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[SCN4A_HUMAN] Postsynaptic congenital myasthenic syndromes;Paramyotonia congenita of Von Eulenburg;Myotonia fluctuans;Hyperkalemic periodic paralysis;Acetazolamide-responsive myotonia;Myotonia permanens;Hypokalemic periodic paralysis. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. SCN4A mutations are the cause of an autosomal recessive neuromuscular disorder characterized by severe fetal hypokinesia, neonatal hypotonia and congenital myopathy of variable severity. The most severe clinical features include reduced or absent fetal movements, in-utero upper and lower limb contractures, talipes and hydrops, and intrauterine or early postnatal death. Mildly affected patients present with generalized hypotonia and weakness at birth or within the first few days of life, mild-to-moderate facial muscle weakness without ptosis, significant early respiratory and feeding difficulties, and skeletal abnormalities of the spine and palate. Symptoms improve over time in patients who survive infancy, resulting in gain of muscle strength and motor skills and concomitant resolution of early respiratory and feeding difficulties. In contrast to other SCN4A-related channelopathies, affected individuals manifest in-utero or neonatal onset of permanent muscle weakness, rather than later-onset episodic muscle weakness.[1]
Function
[SCN4A_HUMAN] This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. This sodium channel may be present in both denervated and innervated skeletal muscle.[2] [3] [CALM1_RAT] 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. Mediates calcium-dependent inactivation of CACNA1C. Positively regulates calcium-activated potassium channel activity of KCNN2.[UniProtKB:P62158]
Publication Abstract from PubMed
Skeletal muscle voltage-gated Na(+) channel (NaV1.4) activity is subject to calmodulin (CaM) mediated Ca(2+)-dependent inactivation; no such inactivation is observed in the cardiac Na(+) channel (NaV1.5). Taken together, the crystal structures of the NaV1.4 C-terminal domain relevant complexes and thermodynamic binding data presented here provide a rationale for this isoform difference. A Ca(2+)-dependent CaM N-lobe binding site previously identified in NaV1.5 is not present in NaV1.4 allowing the N-lobe to signal other regions of the NaV1.4 channel. Consistent with this mechanism, removing this binding site in NaV1.5 unveils robust Ca(2+)-dependent inactivation in the previously insensitive isoform. These findings suggest that Ca(2+)-dependent inactivation is effected by CaM's N-lobe binding outside the NaV C-terminal while CaM's C-lobe remains bound to the NaV C-terminal. As the N-lobe binding motif of NaV1.5 is a mutational hotspot for inherited arrhythmias, the contributions of mutation-induced changes in CDI to arrhythmia generation is an intriguing possibility.
Ca(2+)-dependent regulation of sodium channels NaV1.4 and NaV1.5 is controlled by the post-IQ motif.,Yoder JB, Ben-Johny M, Farinelli F, Srinivasan L, Shoemaker SR, Tomaselli GF, Gabelli SB, Amzel LM Nat Commun. 2019 Apr 3;10(1):1514. doi: 10.1038/s41467-019-09570-7. PMID:30944319[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Zaharieva IT, Thor MG, Oates EC, van Karnebeek C, Hendson G, Blom E, Witting N, Rasmussen M, Gabbett MT, Ravenscroft G, Sframeli M, Suetterlin K, Sarkozy A, D'Argenzio L, Hartley L, Matthews E, Pitt M, Vissing J, Ballegaard M, Krarup C, Slordahl A, Halvorsen H, Ye XC, Zhang LH, Lokken N, Werlauff U, Abdelsayed M, Davis MR, Feng L, Phadke R, Sewry CA, Morgan JE, Laing NG, Vallance H, Ruben P, Hanna MG, Lewis S, Kamsteeg EJ, Mannikko R, Muntoni F. Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or 'classical' congenital myopathy. Brain. 2016 Mar;139(Pt 3):674-91. doi: 10.1093/brain/awv352. Epub 2015 Dec 22. PMID:26700687 doi:http://dx.doi.org/10.1093/brain/awv352
- ↑ Dice MS, Abbruzzese JL, Wheeler JT, Groome JR, Fujimoto E, Ruben PC. Temperature-sensitive defects in paramyotonia congenita mutants R1448C and T1313M. Muscle Nerve. 2004 Sep;30(3):277-88. doi: 10.1002/mus.20080. PMID:15318338 doi:http://dx.doi.org/10.1002/mus.20080
- ↑ Carle T, Lhuillier L, Luce S, Sternberg D, Devuyst O, Fontaine B, Tabti N. Gating defects of a novel Na+ channel mutant causing hypokalemic periodic paralysis. Biochem Biophys Res Commun. 2006 Sep 22;348(2):653-61. doi:, 10.1016/j.bbrc.2006.07.101. Epub 2006 Jul 28. PMID:16890191 doi:http://dx.doi.org/10.1016/j.bbrc.2006.07.101
- ↑ Yoder JB, Ben-Johny M, Farinelli F, Srinivasan L, Shoemaker SR, Tomaselli GF, Gabelli SB, Amzel LM. Ca(2+)-dependent regulation of sodium channels NaV1.4 and NaV1.5 is controlled by the post-IQ motif. Nat Commun. 2019 Apr 3;10(1):1514. doi: 10.1038/s41467-019-09570-7. PMID:30944319 doi:http://dx.doi.org/10.1038/s41467-019-09570-7
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