6agf
Structure of the human voltage-gated sodium channel Nav1.4 in complex with beta1
Structural highlights
DiseaseSCN4A_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] FunctionSCN4A_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] Publication Abstract from PubMedVoltage-gated sodium channels, which are responsible for action potential generation, are implicated in many human diseases. Despite decades of rigorous characterization, the lack of a structure of any human Nav channel has hampered mechanistic understanding. Here we report the cryo-EM structure of human Nav1.4-beta1 complex at 3.2 A resolution. Accurate model building was made for the pore domain, the voltage-sensing domains, and the beta1 subunit, giving insight into the molecular basis for Na(+) permeation and kinetic asymmetry of the four repeats. Structural analysis of reported functional residues and disease mutations corroborates an allosteric blocking mechanism for fast inactivation of Nav channels. The structure provides a path toward mechanistic investigation of Nav channels and drug discovery for Nav channelopathies. Structure of the human voltage-gated sodium channel Nav1.4 in complex with beta1.,Pan X, Li Z, Zhou Q, Shen H, Wu K, Huang X, Chen J, Zhang J, Zhu X, Lei J, Xiong W, Gong H, Xiao B, Yan N Science. 2018 Sep 6. pii: science.aau2486. doi: 10.1126/science.aau2486. PMID:30190309[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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