ID ACHE_HUMAN Reviewed; 493 AA. AC Q04844; D3DTK6; DT 01-FEB-1994, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1995, sequence version 2. DT 09-DEC-2015, entry version 152. DE RecName: Full=Acetylcholine receptor subunit epsilon; DE Flags: Precursor; GN Name=CHRNE; Synonyms=ACHRE; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Muscle fibroblast; RX PubMed=7688301; DOI=10.1111/j.1432-1033.1993.tb18027.x; RA Beeson D.M.W., Brydson M., Betty M., Jeremiah S., Povey S., RA Vincent A., Newsom-Davis J.; RT "Primary structure of the human muscle acetylcholine receptor. cDNA RT cloning of the gamma and epsilon subunits."; RL Eur. J. Biochem. 215:229-238(1993). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Abicht A., Stucka R., Lochmuller H.; RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP VARIANT CMS4A PHE-289. RX PubMed=7538206; DOI=10.1212/WNL.45.5.982; RA Gomez C.M., Gammack J.T.; RT "A leucine-to-phenylalanine substitution in the acetylcholine receptor RT ion channel in a family with the slow-channel syndrome."; RL Neurology 45:982-985(1995). RN [5] RP VARIANT CMS4A PRO-284, AND CHARACTERIZATION OF VARIANT CMS4A PRO-284. RX PubMed=7531341; DOI=10.1073/pnas.92.3.758; RA Ohno K., Hutchinson D.O., Milone M., Brengman J.M., Bouzat C., RA Sine S.M., Engel A.G.; RT "Congenital myasthenic syndrome caused by prolonged acetylcholine RT receptor channel openings due to a mutation in the M2 domain of the RT epsilon subunit."; RL Proc. Natl. Acad. Sci. U.S.A. 92:758-762(1995). RN [6] RP VARIANT CMS4A PHE-289, AND CHARACTERIZATION OF VARIANT CMS4A PHE-289. RX PubMed=8872460; DOI=10.1093/hmg/5.9.1217; RA Engel A.G., Ohno K., Milone M., Wang H.-L., Nakano S., Bouzat C., RA Pruitt J.N. II, Hutchinson D.O., Brengman J.M., Bren N., Sieb J.P., RA Sine S.M.; RT "New mutations in acetylcholine receptor subunit genes reveal RT heterogeneity in the slow-channel congenital myasthenic syndrome."; RL Hum. Mol. Genet. 5:1217-1227(1996). RN [7] RP VARIANTS CMS4B ARG-13; LEU-141 AND LEU-163, AND CHARACTERIZATION OF RP VARIANTS CMS4B ARG-13; LEU-141 AND LEU-163. RX PubMed=8755487; DOI=10.1016/S0896-6273(00)80289-5; RA Ohno K., Wang H.-L., Milone M., Bren N., Brengman J.M., Nakano S., RA Quiram P., Pruitt J.N. II, Sine S.M., Engel A.G.; RT "Congenital myasthenic syndrome caused by decreased agonist binding RT affinity due to a mutation in the acetylcholine receptor epsilon RT subunit."; RL Neuron 17:157-170(1996). RN [8] RP VARIANTS CMS4C LEU-167; LEU-265 AND TRP-331, AND CHARACTERIZATION OF RP VARIANTS CMS4C LEU-167; LEU-265 AND TRP-331. RX PubMed=9158150; DOI=10.1093/hmg/6.5.753; RA Ohno K., Quiram P.A., Milone M., Wang H.-L., Harper M.C., RA Pruitt J.N. II, Brengman J.M., Pao L., Fischbeck K.H., Crawford T.O., RA Sine S.M., Engel A.G.; RT "Congenital myasthenic syndromes due to heteroallelic RT nonsense/missense mutations in the acetylcholine receptor epsilon RT subunit gene: identification and functional characterization of six RT new mutations."; RL Hum. Mol. Genet. 6:753-766(1997). RN [9] RP VARIANT CMS4B PRO-431, AND CHARACTERIZATION OF VARIANT CMS4B PRO-431. RX PubMed=10962020; DOI=10.1085/jgp.116.3.449; RA Wang H.-L., Ohno K., Milone M., Brengman J.M., Evoli A., RA Batocchi A.-P., Middleton L.T., Christodoulou K., Engel A.G., RA Sine S.M.; RT "Fundamental gating mechanism of nicotinic receptor channel revealed RT by mutation causing a congenital myasthenic syndrome."; RL J. Gen. Physiol. 116:449-462(2000). RN [10] RP VARIANTS CMS4A PRO-98 AND PHE-241. RX PubMed=12141316; DOI=10.1212/WNL.59.2.162; RA Croxen R., Hatton C., Shelley C., Brydson M., Chauplannaz G., RA Oosterhuis H., Vincent A., Newsom-Davis J., Colquhoun D., Beeson D.; RT "Recessive inheritance and variable penetrance of slow-channel RT congenital myasthenic syndromes."; RL Neurology 59:162-168(2002). RN [11] RP VARIANT CMS4B ARG-75, AND CHARACTERIZATION OF VARIANT CMS4B ARG-75. RX PubMed=22592360; DOI=10.1212/WNL.0b013e31825b5bda; RA Shen X.M., Brengman J.M., Edvardson S., Sine S.M., Engel A.G.; RT "Highly fatal fast-channel syndrome caused by AChR epsilon subunit RT mutation at the agonist binding site."; RL Neurology 79:449-454(2012). CC -!- FUNCTION: After binding acetylcholine, the AChR responds by an CC extensive change in conformation that affects all subunits and CC leads to opening of an ion-conducting channel across the plasma CC membrane. CC -!- SUBUNIT: Pentamer of two alpha chains, and one each of the beta, CC delta, and gamma (in immature muscle) or epsilon (in mature CC muscle) chains. CC -!- SUBCELLULAR LOCATION: Cell junction, synapse, postsynaptic cell CC membrane; Multi-pass membrane protein. Cell membrane; Multi-pass CC membrane protein. CC -!- DISEASE: Note=The muscle AChR is the major target antigen in the CC autoimmune disease myasthenia gravis. Myasthenia gravis is CC characterized by sporadic muscular fatigability and weakness, CC occurring chiefly in muscles innervated by cranial nerves, and CC characteristically improved by cholinesterase-inhibiting drugs. CC -!- DISEASE: Myasthenic syndrome, congenital, 4A, slow-channel (CMS4A) CC [MIM:605809]: A form of congenital myasthenic syndrome, a group of CC disorders characterized by failure of neuromuscular transmission, CC including pre-synaptic, synaptic, and post-synaptic disorders that CC are not of autoimmune origin. Clinical features are easy CC fatigability and muscle weakness affecting the axial and limb CC muscles (with hypotonia in early-onset forms), the ocular muscles CC (leading to ptosis and ophthalmoplegia), and the facial and bulbar CC musculature (affecting sucking and swallowing, and leading to CC dysphonia). The symptoms fluctuate and worsen with physical CC effort. CMS4A is a slow-channel myasthenic syndrome. It is caused CC by kinetic abnormalities of the AChR, resulting in prolonged AChR CC channel opening episodes, prolonged endplate currents, and CC depolarization block. This is associated with calcium overload, CC which may contribute to subsequent degeneration of the endplate CC and postsynaptic membrane. {ECO:0000269|PubMed:12141316, CC ECO:0000269|PubMed:7531341, ECO:0000269|PubMed:7538206, CC ECO:0000269|PubMed:8872460}. Note=The disease is caused by CC mutations affecting the gene represented in this entry. CC -!- DISEASE: Myasthenic syndrome, congenital, 4B, fast-channel (CMS4B) CC [MIM:616324]: A form of congenital myasthenic syndrome, a group of CC disorders characterized by failure of neuromuscular transmission, CC including pre-synaptic, synaptic, and post-synaptic disorders that CC are not of autoimmune origin. Clinical features are easy CC fatigability and muscle weakness affecting the axial and limb CC muscles (with hypotonia in early-onset forms), the ocular muscles CC (leading to ptosis and ophthalmoplegia), and the facial and bulbar CC musculature (affecting sucking and swallowing, and leading to CC dysphonia). The symptoms fluctuate and worsen with physical CC effort. CMS4B is a fast-channel myasthenic syndrome. It is caused CC by kinetic abnormalities of the AChR, resulting in brief opening CC and activity of the channel, with a rapid decay in endplate CC current, failure to achieve threshold depolarization of the CC endplate and consequent failure to fire an action potential. CC {ECO:0000269|PubMed:10962020, ECO:0000269|PubMed:22592360, CC ECO:0000269|PubMed:8755487}. Note=The disease is caused by CC mutations affecting the gene represented in this entry. CC -!- DISEASE: Myasthenic syndrome, congenital, 4C, associated with CC acetylcholine receptor deficiency (CMS4C) [MIM:608931]: A form of CC congenital myasthenic syndrome, a group of disorders characterized CC by failure of neuromuscular transmission, including pre-synaptic, CC synaptic, and post-synaptic disorders that are not of autoimmune CC origin. Clinical features are easy fatigability and muscle CC weakness affecting the axial and limb muscles (with hypotonia in CC early-onset forms), the ocular muscles (leading to ptosis and CC ophthalmoplegia), and the facial and bulbar musculature (affecting CC sucking and swallowing, and leading to dysphonia). The symptoms CC fluctuate and worsen with physical effort. CMS4C is an autosomal CC recessive disorder of postsynaptic neuromuscular transmission, due CC to deficiency of AChR at the endplate that results in low CC amplitude of the miniature endplate potential and current. CC {ECO:0000269|PubMed:9158150}. Note=The disease is caused by CC mutations affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the ligand-gated ion channel (TC 1.A.9) CC family. Acetylcholine receptor (TC 1.A.9.1) subfamily. CC Epsilon/CHRNE sub-subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X66403; CAA47030.1; -; mRNA. DR EMBL; AF105999; AAD24503.1; -; Genomic_DNA. DR EMBL; CH471108; EAW90395.1; -; Genomic_DNA. DR EMBL; CH471108; EAW90396.1; -; Genomic_DNA. DR CCDS; CCDS11058.1; -. DR PIR; S34775; S34775. DR RefSeq; NP_000071.1; NM_000080.3. DR UniGene; Hs.654535; -. DR PDB; 2DF9; Model; -; A=240-332. DR PDBsum; 2DF9; -. DR ProteinModelPortal; Q04844; -. DR SMR; Q04844; 22-337, 418-485. DR BioGrid; 107567; 1. DR STRING; 9606.ENSP00000293780; -. DR BindingDB; Q04844; -. DR ChEMBL; CHEMBL2362997; -. DR DrugBank; DB00674; Galantamine. DR GuidetoPHARMACOLOGY; 477; -. DR TCDB; 1.A.9.1.1; the neurotransmitter receptor, cys loop, ligand-gated ion channel (lic) family. DR BioMuta; CHRNE; -. DR DMDM; 1168301; -. DR PaxDb; Q04844; -. DR PRIDE; Q04844; -. DR Ensembl; ENST00000293780; ENSP00000293780; ENSG00000108556. DR GeneID; 1145; -. DR KEGG; hsa:1145; -. DR UCSC; uc002fzk.1; human. DR CTD; 1145; -. DR GeneCards; CHRNE; -. DR GeneReviews; CHRNE; -. DR H-InvDB; HIX0027273; -. DR HGNC; HGNC:1966; CHRNE. DR MalaCards; CHRNE; -. DR MIM; 100725; gene. DR MIM; 254200; phenotype. DR MIM; 605809; phenotype. DR MIM; 608931; phenotype. DR MIM; 616324; phenotype. DR neXtProt; NX_Q04844; -. DR Orphanet; 98913; Postsynaptic congenital myasthenic syndromes. DR PharmGKB; PA26498; -. DR eggNOG; KOG3645; Eukaryota. DR eggNOG; ENOG410XQGR; LUCA. DR GeneTree; ENSGT00760000118930; -. DR HOGENOM; HOG000006757; -. DR HOVERGEN; HBG003756; -. DR InParanoid; Q04844; -. DR KO; K04817; -. DR OMA; RHRHGTW; -. DR OrthoDB; EOG7H7925; -. DR PhylomeDB; Q04844; -. DR TreeFam; TF315605; -. DR Reactome; R-HSA-629587; Highly sodium permeable acetylcholine nicotinic receptors. DR GeneWiki; CHRNE; -. DR GenomeRNAi; 1145; -. DR NextBio; 4764; -. DR PRO; PR:Q04844; -. DR Proteomes; UP000005640; Chromosome 17. DR Bgee; Q04844; -. DR CleanEx; HS_CHRNE; -. DR Genevisible; Q04844; HS. DR GO; GO:0005892; C:acetylcholine-gated channel complex; TAS:ProtInc. DR GO; GO:0030054; C:cell junction; IEA:UniProtKB-KW. DR GO; GO:0005887; C:integral component of plasma membrane; TAS:ProtInc. DR GO; GO:0043005; C:neuron projection; IBA:GO_Central. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0045211; C:postsynaptic membrane; IEA:UniProtKB-SubCell. DR GO; GO:0045202; C:synapse; IBA:GO_Central. DR GO; GO:0015464; F:acetylcholine receptor activity; TAS:ProtInc. DR GO; GO:0004889; F:acetylcholine-activated cation-selective channel activity; TAS:ProtInc. DR GO; GO:0008324; F:cation transmembrane transporter activity; TAS:ProtInc. DR GO; GO:0098655; P:cation transmembrane transport; TAS:GOC. DR GO; GO:0006936; P:muscle contraction; TAS:ProtInc. DR GO; GO:0050877; P:neurological system process; IBA:GO_Central. DR GO; GO:0007274; P:neuromuscular synaptic transmission; IBA:GO_Central. DR GO; GO:0042391; P:regulation of membrane potential; IBA:GO_Central. DR GO; GO:0035094; P:response to nicotine; IBA:GO_Central. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR GO; GO:0003009; P:skeletal muscle contraction; IEA:Ensembl. DR GO; GO:0007268; P:synaptic transmission; TAS:Reactome. DR GO; GO:0007271; P:synaptic transmission, cholinergic; TAS:ProtInc. DR GO; GO:0006810; P:transport; TAS:ProtInc. DR Gene3D; 1.20.120.370; -; 2. DR Gene3D; 2.70.170.10; -; 1. DR InterPro; IPR027361; Acetylcholine_rcpt_TM. DR InterPro; IPR006202; Neur_chan_lig-bd. DR InterPro; IPR006201; Neur_channel. DR InterPro; IPR006029; Neurotrans-gated_channel_TM. DR InterPro; IPR018000; Neurotransmitter_ion_chnl_CS. DR InterPro; IPR002394; Nicotinic_acetylcholine_rcpt. DR PANTHER; PTHR18945; PTHR18945; 2. DR Pfam; PF02931; Neur_chan_LBD; 1. DR Pfam; PF02932; Neur_chan_memb; 1. DR PRINTS; PR00254; NICOTINICR. DR PRINTS; PR00252; NRIONCHANNEL. DR SUPFAM; SSF63712; SSF63712; 1. DR SUPFAM; SSF90112; SSF90112; 1. DR PROSITE; PS00236; NEUROTR_ION_CHANNEL; 1. PE 1: Evidence at protein level; KW 3D-structure; Cell junction; Cell membrane; Complete proteome; KW Congenital myasthenic syndrome; Disease mutation; Disulfide bond; KW Glycoprotein; Ion channel; Ion transport; Ligand-gated ion channel; KW Membrane; Polymorphism; Postsynaptic cell membrane; Receptor; KW Reference proteome; Signal; Synapse; Transmembrane; KW Transmembrane helix; Transport. FT SIGNAL 1 20 FT CHAIN 21 493 Acetylcholine receptor subunit epsilon. FT /FTId=PRO_0000000329. FT TOPO_DOM 21 239 Extracellular. {ECO:0000255}. FT TRANSMEM 240 264 Helical. {ECO:0000255}. FT TOPO_DOM 265 272 Cytoplasmic. {ECO:0000255}. FT TRANSMEM 273 291 Helical. {ECO:0000255}. FT TOPO_DOM 292 306 Extracellular. {ECO:0000255}. FT TRANSMEM 307 328 Helical. {ECO:0000255}. FT TOPO_DOM 329 456 Cytoplasmic. {ECO:0000255}. FT TRANSMEM 457 480 Helical. {ECO:0000255}. FT TOPO_DOM 481 493 Extracellular. {ECO:0000255}. FT CARBOHYD 86 86 N-linked (GlcNAc...). {ECO:0000255}. FT CARBOHYD 161 161 N-linked (GlcNAc...). {ECO:0000255}. FT DISULFID 148 162 {ECO:0000250}. FT VARIANT 13 13 G -> R (in CMS4B; impaired association FT with alpha CHRNA1 subunit of AChR). FT {ECO:0000269|PubMed:8755487}. FT /FTId=VAR_021213. FT VARIANT 18 18 G -> V (in dbSNP:rs4790235). FT /FTId=VAR_048170. FT VARIANT 75 75 W -> R (in CMS4B; strongly reduces FT agonist affinity and gating efficiency). FT {ECO:0000269|PubMed:22592360}. FT /FTId=VAR_071629. FT VARIANT 98 98 L -> P (in CMS4A; rare example of FT recessive inheritance; dbSNP:rs28929768). FT {ECO:0000269|PubMed:12141316}. FT /FTId=VAR_019567. FT VARIANT 141 141 P -> L (in CMS4B; marked decrease in rate FT of AChR channel opening; reduction in FT frequency of open channel state and FT resistance to desensitization by ACh). FT {ECO:0000269|PubMed:8755487}. FT /FTId=VAR_000289. FT VARIANT 163 163 S -> L (in CMS4B; fails to assemble with FT alpha CHRNA1 subunit of AChR). FT {ECO:0000269|PubMed:8755487}. FT /FTId=VAR_021214. FT VARIANT 167 167 R -> L (in CMS4C; significantly reduced FT AChR expression). FT {ECO:0000269|PubMed:9158150}. FT /FTId=VAR_000290. FT VARIANT 241 241 L -> F (in CMS4A; mild form with variable FT penetrance; dbSNP:rs28999110). FT {ECO:0000269|PubMed:12141316}. FT /FTId=VAR_019568. FT VARIANT 265 265 P -> L (in CMS4C; prolongs burst open FT duration 2-fold by slowing the rate of FT channel closing). FT {ECO:0000269|PubMed:9158150}. FT /FTId=VAR_000291. FT VARIANT 284 284 T -> P (in CMS4A; markedly prolonged FT channel openings in presence of agonist; FT as well as opening in the absence of FT agonist). {ECO:0000269|PubMed:7531341}. FT /FTId=VAR_000292. FT VARIANT 289 289 L -> F (in CMS4A; slows rate of AChR FT channel closure and increases apparent FT affinity for ACh; causes pathologic FT channel openings even in the absence of FT ACh resulting in a leaky channel). FT {ECO:0000269|PubMed:7538206, FT ECO:0000269|PubMed:8872460}. FT /FTId=VAR_000293. FT VARIANT 331 331 R -> W (in CMS4C; shortens burst duration FT 2-fold by slowing the rate of channel FT opening and speeding the rate of ACh FT dissociation; has a mild fast-channel FT kinetic effect on the AChR by shortening FT the long burst and increasing the decay FT of the endplate current). FT {ECO:0000269|PubMed:9158150}. FT /FTId=VAR_000294. FT VARIANT 431 431 A -> P (in CMS4B; causes an increase in FT distributions of rates for channel FT opening and closing increasing the range FT of activation kinetics). FT {ECO:0000269|PubMed:10962020}. FT /FTId=VAR_021215. SQ SEQUENCE 493 AA; 54697 MW; A34AF273AF8B31FE CRC64; MARAPLGVLL LLGLLGRGVG KNEELRLYHH LFNNYDPGSR PVREPEDTVT ISLKVTLTNL ISLNEKEETL TTSVWIGIDW QDYRLNYSKD DFGGIETLRV PSELVWLPEI VLENNIDGQF GVAYDANVLV YEGGSVTWLP PAIYRSVCAV EVTYFPFDWQ NCSLIFRSQT YNAEEVEFTF AVDNDGKTIN KIDIDTEAYT ENGEWAIDFC PGVIRRHHGG ATDGPGETDV IYSLIIRRKP LFYVINIIVP CVLISGLVLL AYFLPAQAGG QKCTVSINVL LAQTVFLFLI AQKIPETSLS VPLLGRFLIF VMVVATLIVM NCVIVLNVSQ RTPTTHAMSP RLRHVLLELL PRLLGSPPPP EAPRAASPPR RASSVGLLLR AEELILKKPR SELVFEGQRH RQGTWTAAFC QSLGAAAPEV RCCVDAVNFV AESTRDQEAT GEEVSDWVRM GNALDNICFW AALVLFSVGS SLIFLGAYFN RVPDLPYAPC IQP //