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P43681 (ACHA4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 152. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Neuronal acetylcholine receptor subunit alpha-4
Gene names
Name:CHRNA4
Synonyms:NACRA4
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length627 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeable to sodium ions. Ref.10

Subunit structure

Neuronal AChR is composed of two different types of subunits: alpha and beta. Alpha-4 subunit can be combined to beta-2 or beta-4 to give rise to functional receptors, complexes with beta-2 may be heteropentamers. Interacts with RIC3; which is required for proper folding and assembly. Ref.9 Ref.10

Subcellular location

Cell junctionsynapsepostsynaptic cell membrane; Multi-pass membrane protein. Cell membrane; Multi-pass membrane protein. Cell membrane; Lipid-anchor By similarity.

Involvement in disease

Epilepsy, nocturnal frontal lobe, 1 (ENFL1) [MIM:600513]: An autosomal dominant focal epilepsy characterized by nocturnal seizures with hyperkinetic automatisms and poorly organized stereotyped movements.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.11 Ref.12 Ref.13

Sequence similarities

Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Alpha-4/CHRNA4 sub-subfamily. [View classification]

Ontologies

Keywords
   Biological processIon transport
Transport
   Cellular componentCell junction
Cell membrane
Membrane
Postsynaptic cell membrane
Synapse
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDisease mutation
Epilepsy
   DomainSignal
Transmembrane
Transmembrane helix
   Molecular functionIon channel
Ligand-gated ion channel
Receptor
   PTMDisulfide bond
Glycoprotein
Lipoprotein
Palmitate
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processB cell activation

Inferred from sequence or structural similarity. Source: UniProtKB

DNA repair

Inferred from mutant phenotype PubMed 16332175. Source: UniProtKB

action potential

Inferred from sequence or structural similarity. Source: UniProtKB

behavioral response to nicotine

Inferred from mutant phenotype PubMed 17955458. Source: UniProtKB

calcium ion transport

Inferred from sequence or structural similarity. Source: UniProtKB

cognition

Inferred from mutant phenotype Ref.13. Source: UniProtKB

exploration behavior

Inferred from electronic annotation. Source: Ensembl

ion transmembrane transport

Traceable author statement PubMed 20438829. Source: GOC

ion transport

Non-traceable author statement Ref.3. Source: UniProtKB

locomotory behavior

Inferred from electronic annotation. Source: Ensembl

membrane depolarization

Inferred from sequence or structural similarity. Source: UniProtKB

neurological system process

Inferred from mutant phenotype PubMed 17613539Ref.11. Source: UniProtKB

regulation of dopamine secretion

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of inhibitory postsynaptic membrane potential

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of membrane potential

Inferred from sequence or structural similarity. Source: UniProtKB

respiratory gaseous exchange

Inferred from electronic annotation. Source: Ensembl

response to hypoxia

Inferred from direct assay PubMed 12189247. Source: UniProtKB

response to nicotine

Inferred from direct assay PubMed 12189247. Source: UniProtKB

response to oxidative stress

Inferred from mutant phenotype PubMed 16332175. Source: UniProtKB

sensory perception of pain

Inferred from sequence or structural similarity. Source: UniProtKB

signal transduction

Inferred from direct assay Ref.3. Source: UniProtKB

synaptic transmission

Non-traceable author statement Ref.11. Source: UniProtKB

synaptic transmission, cholinergic

Inferred from sequence or structural similarity. Source: UniProtKB

   Cellular_componentacetylcholine-gated channel complex

Inferred from direct assay Ref.3. Source: UniProtKB

cell junction

Inferred from electronic annotation. Source: UniProtKB-KW

dendrite

Inferred from sequence or structural similarity. Source: UniProtKB

external side of plasma membrane

Inferred from sequence or structural similarity. Source: UniProtKB

integral component of membrane

Non-traceable author statement Ref.3. Source: UniProtKB

membrane

Inferred from sequence or structural similarity. Source: UniProtKB

neuronal cell body

Inferred from sequence or structural similarity. Source: UniProtKB

plasma membrane

Inferred from sequence or structural similarity. Source: UniProtKB

postsynaptic membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionacetylcholine binding

Inferred by curator Ref.3. Source: UniProtKB

acetylcholine receptor activity

Inferred from direct assay Ref.3. Source: UniProtKB

acetylcholine-activated cation-selective channel activity

Inferred from direct assay Ref.3. Source: UniProtKB

ligand-gated ion channel activity

Traceable author statement PubMed 20438829. Source: DFLAT

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P43681-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: P43681-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-57: MELGGPGAPR...YNKWSRPVAN → MRMSPPSASP...VWTAGCPGEG
     58-128: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2828 Potential
Chain29 – 627599Neuronal acetylcholine receptor subunit alpha-4
PRO_0000000351

Regions

Topological domain29 – 242214Extracellular Potential
Transmembrane243 – 26725Helical; Potential
Transmembrane275 – 29319Helical; Potential
Transmembrane309 – 33022Helical; Potential
Topological domain331 – 600270Cytoplasmic Potential
Transmembrane601 – 61919Helical; Potential

Amino acid modifications

Lipidation2711S-palmitoyl cysteine By similarity
Glycosylation571N-linked (GlcNAc...) Potential
Glycosylation1071N-linked (GlcNAc...) Potential
Glycosylation1741N-linked (GlcNAc...) Potential
Disulfide bond161 ↔ 175 By similarity
Disulfide bond225 ↔ 226Associated with receptor activation By similarity

Natural variations

Alternative sequence1 – 5757MELGG…RPVAN → MRMSPPSASPPSSSGGRTSS STTTAGEPFWAGVLFAIRPH PGLSGRIVWTAGCPGEG in isoform 2.
VSP_054275
Alternative sequence58 – 12871Missing in isoform 2.
VSP_054276
Natural variant2801S → F in ENFL1. Ref.11
VAR_000295
Natural variant2801S → L in ENFL1. Ref.12 Ref.13
VAR_017531
Natural variant3871E → G. Ref.5
Corresponds to variant rs45604738 [ dbSNP | Ensembl ].
VAR_023402
Natural variant5171S → L. Ref.5
Corresponds to variant rs45622132 [ dbSNP | Ensembl ].
VAR_023403

Experimental info

Sequence conflict41G → E in AAH96290. Ref.7

Secondary structure

............. 627
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified February 1, 1996. Version 2.
Checksum: B3A0C0151E5A2AA8

FASTA62769,957
        10         20         30         40         50         60 
MELGGPGAPR LLPPLLLLLG TGLLRASSHV ETRAHAEERL LKKLFSGYNK WSRPVANISD 

        70         80         90        100        110        120 
VVLVRFGLSI AQLIDVDEKN QMMTTNVWVK QEWHDYKLRW DPADYENVTS IRIPSELIWR 

       130        140        150        160        170        180 
PDIVLYNNAD GDFAVTHLTK AHLFHDGRVQ WTPPAIYKSS CSIDVTFFPF DQQNCTMKFG 

       190        200        210        220        230        240 
SWTYDKAKID LVNMHSRVDQ LDFWESGEWV IVDAVGTYNT RKYECCAEIY PDITYAFVIR 

       250        260        270        280        290        300 
RLPLFYTINL IIPCLLISCL TVLVFYLPSE CGEKITLCIS VLLSLTVFLL LITEIIPSTS 

       310        320        330        340        350        360 
LVIPLIGEYL LFTMIFVTLS IVITVFVLNV HHRSPRTHTM PTWVRRVFLD IVPRLLLMKR 

       370        380        390        400        410        420 
PSVVKDNCRR LIESMHKMAS APRFWPEPEG EPPATSGTQS LHPPSPSFCV PLDVPAEPGP 

       430        440        450        460        470        480 
SCKSPSDQLP PQQPLEAEKA SPHPSPGPCR PPHGTQAPGL AKARSLSVQH MSSPGEAVEG 

       490        500        510        520        530        540 
GVRCRSRSIQ YCVPRDDAAP EADGQAAGAL ASRNTHSAEL PPPDQPSPCK CTCKKEPSSV 

       550        560        570        580        590        600 
SPSATVKTRS TKAPPPHLPL SPALTRAVEG VQYIADHLKA EDTDFSVKED WKYVAMVIDR 

       610        620 
IFLWMFIIVC LLGTVGLFLP PWLAGMI 

« Hide

Isoform 2 [UniParc].

Checksum: CE5902DBC1231CA3
Show »

FASTA55660,994

References

« Hide 'large scale' references
[1]"Cloning and transient expression of genes encoding the human alpha-4 and beta-2 neuronal nicotinic acetylcholine receptor (nAChR) subunits."
Monteggia L.M., Gopalakrishnan M., Touma E., Idler K.B., Nash N., Arneric S.P., Sullivan J.P., Giordano T.
Gene 155:189-193(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Brain.
[2]"Exon-intron structure of the human neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4)."
Steinlein O.K., Weiland S., Stood J., Propping P.
Genomics 32:289-294(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]"Comparative structure of human neuronal alpha 2-alpha 7 and beta 2-beta 4 nicotinic acetylcholine receptor subunits and functional expression of the alpha 2, alpha 3, alpha 4, alpha 7, beta 2, and beta 4 subunits."
Elliott K.J., Ellis S.B., Berckhan K.J., Urrutia A., Chavez-Noriega L.E., Johnson E.C., Velicelebi G., Harpold M.M.
J. Mol. Neurosci. 7:217-228(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Hippocampus.
[4]"Cloning and sequence of full-length cDNAs encoding the human neuronal nicotinic acetylcholine receptor (nAChR) subunits beta3 and beta4 and expression of seven nAChR subunits in the human neuroblastoma cell line SH-SY5Y and/or IMR-32."
Groot Kormelink P.J., Luyten W.H.M.L.
FEBS Lett. 400:309-314(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[5]NIEHS SNPs program
Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS GLY-387 AND LEU-517.
[6]"The DNA sequence and comparative analysis of human chromosome 20."
Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., Bird C.P., Blakey S.E. expand/collapse author list , Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.
Nature 414:865-871(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
[8]"Molecular cloning of human neuronal nicotinic acetylcholine receptor 4-like subunit."
Mamalaki A., Remoundos M., Tzartos S.
Submitted (MAY-1995) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 26-627 (ISOFORM 1).
Tissue: Brain.
[9]"RIC-3 enhances functional expression of multiple nicotinic acetylcholine receptor subtypes in mammalian cells."
Lansdell S.J., Gee V.J., Harkness P.C., Doward A.I., Baker E.R., Gibb A.J., Millar N.S.
Mol. Pharmacol. 68:1431-1438(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RIC3.
[10]"NMR structures of the transmembrane domains of the alpha4beta2 nAChR."
Bondarenko V., Mowrey D., Tillman T., Cui T., Liu L.T., Xu Y., Tang P.
Biochim. Biophys. Acta 1818:1261-1268(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE BY NMR OF 242-625, SUBUNIT, FUNCTION.
[11]"A missense mutation in the neuronal nicotinic acetylcholine receptor alpha-4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy."
Steinlein O.K., Mulley J.C., Propping P., Wallace R.H., Phillips H.A., Sutherland G.R., Scheffer I.E., Berkovic S.F.
Nat. Genet. 11:201-203(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT ENFL1 PHE-280.
[12]"A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy."
Hirose S., Iwata H., Akiyoshi H., Kobayashi K., Ito M., Wada K., Kaneko S., Mitsudome A.
Neurology 53:1749-1753(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT ENFL1 LEU-280.
[13]"A Korean kindred with autosomal dominant nocturnal frontal lobe epilepsy and mental retardation."
Cho Y.-W., Motamedi G.K., Laufenberg I., Sohn S.-I., Lim J.-G., Lee H., Yi S.-D., Lee J.-H., Kim D.-K., Reba R., Gaillard W.D., Theodore W.H., Lesser R.P., Steinlein O.K.
Arch. Neurol. 60:1625-1632(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT ENFL1 LEU-280.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L35901 mRNA. Translation: AAA64743.1.
X89741 expand/collapse EMBL AC list , X89742, X89743, X89744, X89745, X89746 Genomic DNA. Translation: CAA61893.1.
U62433 mRNA. Translation: AAB40111.1.
Y08421 mRNA. Translation: CAA69698.1.
DQ093071 Genomic DNA. Translation: AAY88737.1.
AL121827 Genomic DNA. No translation available.
BC096290 mRNA. Translation: AAH96290.1.
BC096291 mRNA. Translation: AAH96291.1.
X87629 mRNA. Translation: CAA60959.1.
CCDSCCDS13517.1.
PIRJC4021.
RefSeqNP_000735.1. NM_000744.6. [P43681-1]
NP_001243502.1. NM_001256573.1.
UniGeneHs.10734.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2GVTmodel-A/C38-241[»]
2LLYNMR-A240-339[»]
A598-626[»]
ProteinModelPortalP43681.
SMRP43681. Positions 37-339, 598-625.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid107559. 3 interactions.
IntActP43681. 1 interaction.
MINTMINT-3015931.
STRING9606.ENSP00000359285.

Chemistry

BindingDBP43681.
ChEMBLCHEMBL3038461.
DrugBankDB00184. Nicotine.
DB01273. Varenicline.
GuidetoPHARMACOLOGY465.

Protein family/group databases

TCDB1.A.9.1.6. the neurotransmitter receptor, cys loop, ligand-gated ion channel (lic) family.

PTM databases

PhosphoSiteP43681.

Polymorphism databases

DMDM1351848.

Proteomic databases

PaxDbP43681.
PRIDEP43681.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000370263; ENSP00000359285; ENSG00000101204.
GeneID1137.
KEGGhsa:1137.
UCSCuc002yes.3. human. [P43681-1]

Organism-specific databases

CTD1137.
GeneCardsGC20M061974.
GeneReviewsCHRNA4.
HGNCHGNC:1958. CHRNA4.
HPACAB034064.
MIM118504. gene.
600513. phenotype.
neXtProtNX_P43681.
Orphanet98784. Autosomal dominant nocturnal frontal lobe epilepsy.
PharmGKBPA26490.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG290206.
HOGENOMHOG000006756.
HOVERGENHBG003756.
InParanoidP43681.
KOK04806.
OMASFCVPLD.
OrthoDBEOG72JWGV.
PhylomeDBP43681.
TreeFamTF315605.

Enzyme and pathway databases

ReactomeREACT_13685. Neuronal System.

Gene expression databases

ArrayExpressP43681.
BgeeP43681.
CleanExHS_CHRNA4.
GenevestigatorP43681.

Family and domain databases

Gene3D1.20.120.370. 2 hits.
2.70.170.10. 1 hit.
InterProIPR027361. Acetylcholine_rcpt_TM.
IPR006202. Neur_chan_lig-bd.
IPR006201. Neur_channel.
IPR006029. Neurotrans-gated_channel_TM.
IPR018000. Neurotransmitter_ion_chnl_CS.
IPR002394. Nicotinic_acetylcholine_rcpt.
[Graphical view]
PANTHERPTHR18945. PTHR18945. 1 hit.
PfamPF02931. Neur_chan_LBD. 1 hit.
PF02932. Neur_chan_memb. 1 hit.
[Graphical view]
PRINTSPR00254. NICOTINICR.
PR00252. NRIONCHANNEL.
SUPFAMSSF63712. SSF63712. 1 hit.
SSF90112. SSF90112. 2 hits.
TIGRFAMsTIGR00860. LIC. 1 hit.
PROSITEPS00236. NEUROTR_ION_CHANNEL. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiCHRNA4.
GenomeRNAi1137.
NextBio4730.
PROP43681.
SOURCESearch...

Entry information

Entry nameACHA4_HUMAN
AccessionPrimary (citable) accession number: P43681
Secondary accession number(s): Q4JGR7, Q4VAQ5, Q4VAQ6
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: February 1, 1996
Last modified: July 9, 2014
This is version 152 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 20

Human chromosome 20: entries, gene names and cross-references to MIM