7sx4
Human NALCN-FAM155A-UNC79-UNC80 channelosome with CaM bound, conformation 2/2
Structural highlights
DiseaseNALCN_HUMAN Freeman-Sheldon syndrome;Congenital limbs-face contractures-hypotonia-developmental delay syndrome;Distal arthrogryposis type 1;Hypotonia-speech impairment-severe cognitive delay syndrome;Sheldon-Hall syndrome. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. FunctionNALCN_HUMAN Voltage-gated ion channel responsible for the resting Na(+) permeability that controls neuronal excitability (PubMed:17448995, PubMed:31409833). NALCN channel functions as a multi-protein complex, which consists at least of NALCN, NALF1, UNC79 and UNC80 (PubMed:32494638, PubMed:33203861). NALCN is the voltage-sensing, pore-forming subunit of the NALCN channel complex (PubMed:17448995). NALCN channel complex is constitutively active and conducts monovalent cations but is blocked by physiological concentrations of extracellular divalent cations (PubMed:32494638). In addition to its role in regulating neuronal excitability, is required for normal respiratory rhythm, systemic osmoregulation by controlling the serum sodium concentration and in the regulation of the intestinal pace-making activity in the interstitial cells of Cajal (By similarity). NALCN channel is also activated by neuropeptides such as neurotensin and substance P (SP) through a SRC family kinases-dependent pathway (By similarity). In addition, NALCN activity is enhanced/modulated by several GPCRs, such as CHRM3 (By similarity).[UniProtKB:Q8BXR5][1] [2] [3] [4] Publication Abstract from PubMedDepolarizing sodium (Na(+)) leak currents carried by the NALCN channel regulate the resting membrane potential of many neurons to modulate respiration, circadian rhythm, locomotion and pain sensitivity(1-8). NALCN requires FAM155A, UNC79 and UNC80 to function, but the role of these auxiliary subunits is not understood(3,7,9-12). NALCN, UNC79 and UNC80 are essential in rodents(2,9,13), and mutations in human NALCN and UNC80 cause severe developmental and neurological disease(14,15). Here we determined the structure of the NALCN channelosome, an approximately 1-MDa complex, as fundamental aspects about the composition, assembly and gating of this channelosome remain obscure. UNC79 and UNC80 are massive HEAT-repeat proteins that form an intertwined anti-parallel superhelical assembly, which docks intracellularly onto the NALCN-FAM155A pore-forming subcomplex. Calmodulin copurifies bound to the carboxy-terminal domain of NALCN, identifying this region as a putative modulatory hub. Single-channel analyses uncovered a low open probability for the wild-type complex, highlighting the tightly closed S6 gate in the structure, and providing a basis to interpret the altered gating properties of disease-causing variants. Key constraints between the UNC79-UNC80 subcomplex and the NALCN DI-DII and DII-DIII linkers were identified, leading to a model of channelosome gating. Our results provide a structural blueprint to understand the physiology of the NALCN channelosome and a template for drug discovery to modulate the resting membrane potential. Structural architecture of the human NALCN channelosome.,Kschonsak M, Chua HC, Weidling C, Chakouri N, Noland CL, Schott K, Chang T, Tam C, Patel N, Arthur CP, Leitner A, Ben-Johny M, Ciferri C, Pless SA, Payandeh J Nature. 2022 Mar;603(7899):180-186. doi: 10.1038/s41586-021-04313-5. Epub 2021 , Dec 20. PMID:34929720[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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