6xiw
From Proteopedia
Cryo-EM structure of the sodium leak channel NALCN-FAM155A complex
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 PubMedPersistently depolarizing sodium (Na(+)) leak currents enhance electrical excitability(1,2). The ion channel responsible for the major background Na(+) conductance in neurons is the Na(+) leak channel, non-selective (NALCN)(3,4). NALCN-mediated currents regulate neuronal excitability linked to respiration, locomotion and circadian rhythm(4-10). NALCN activity is under tight regulation(11-14) and mutations in NALCN cause severe neurological disorders and early death(15,16). NALCN is an orphan channel in humans, and fundamental aspects of channel assembly, gating, ion selectivity and pharmacology remain obscure. Here we investigate this essential leak channel and determined the structure of NALCN in complex with a distinct auxiliary subunit, family with sequence similarity 155 member A (FAM155A). FAM155A forms an extracellular dome that shields the ion-selectivity filter from neurotoxin attack. The pharmacology of NALCN is further delineated by a walled-off central cavity with occluded lateral pore fenestrations. Unusual voltage-sensor domains with asymmetric linkages to the pore suggest mechanisms by which NALCN activity is modulated. We found a tightly closed pore gate in NALCN where the majority of missense patient mutations cause gain-of-function phenotypes that cluster around the S6 gate and distinctive pi-bulges. Our findings provide a framework to further study the physiology of NALCN and a foundation for discovery of treatments for NALCN channelopathies and other electrical disorders. Structure of the human sodium leak channel NALCN.,Kschonsak M, Chua HC, Noland CL, Weidling C, Clairfeuille T, Bahlke OO, Ameen AO, Li ZR, Arthur CP, Ciferri C, Pless SA, Payandeh J Nature. 2020 Nov;587(7833):313-318. doi: 10.1038/s41586-020-2570-8. Epub 2020 Jul , 22. PMID:32698188[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
Categories: Homo sapiens | Large Structures | Ameen AO | Arthur CP | Bahlke OO | Chua HC | Ciferri C | Clairfeuille T | Kschonsak M | Li ZR | Noland CL | Payandeh J | Pless SA | Weidling C
