UniProtKB - P37088 (SCNNA_HUMAN)
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Protein
Amiloride-sensitive sodium channel subunit alpha
Gene
SCNN1A
Organism
Homo sapiens (Human)
Status
Functioni
Sodium permeable non-voltage-sensitive ion channel inhibited by the diuretic amiloride. Mediates the electrodiffusion of the luminal sodium (and water, which follows osmotically) through the apical membrane of epithelial cells. Plays an essential role in electrolyte and blood pressure homeostasis, but also in airway surface liquid homeostasis, which is important for proper clearance of mucus. Controls the reabsorption of sodium in kidney, colon, lung and eccrine sweat glands. Also plays a role in taste perception.2 Publications
Enzyme regulationi
Activated by WNK1, WNK2, WNK3 and WNK4.By similarity
GO - Molecular functioni
- ligand-gated sodium channel activity Source: InterPro
- WW domain binding Source: BHF-UCL
GO - Biological processi
- ion transmembrane transport Source: Reactome
- multicellular organismal water homeostasis Source: UniProtKB
- response to stimulus Source: UniProtKB-KW
- sensory perception of taste Source: UniProtKB-KW
- sodium ion homeostasis Source: UniProtKB
- sodium ion transmembrane transport Source: UniProtKB
Keywordsi
Molecular function | Ion channel, Sodium channel |
Biological process | Ion transport, Sensory transduction, Sodium transport, Taste, Transport |
Ligand | Sodium |
Enzyme and pathway databases
Reactomei | R-HSA-2672351. Stimuli-sensing channels. |
SIGNORi | P37088. |
Protein family/group databases
TCDBi | 1.A.6.1.1. the epithelial na(+) channel (enac) family. |
Names & Taxonomyi
Protein namesi | Recommended name: Amiloride-sensitive sodium channel subunit alphaAlternative name(s): Alpha-NaCH Epithelial Na(+) channel subunit alpha Short name: Alpha-ENaC Short name: ENaCA Nonvoltage-gated sodium channel 1 subunit alpha SCNEA |
Gene namesi | Name:SCNN1A Synonyms:SCNN1 |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
EuPathDBi | HostDB:ENSG00000111319.12. |
HGNCi | HGNC:10599. SCNN1A. |
MIMi | 600228. gene. |
neXtProti | NX_P37088. |
Subcellular locationi
Topology
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Topological domaini | 1 – 85 | CytoplasmicBy similarityAdd BLAST | 85 | |
Transmembranei | 86 – 106 | Helical; Name=1Sequence analysisAdd BLAST | 21 | |
Topological domaini | 107 – 562 | ExtracellularBy similarityAdd BLAST | 456 | |
Transmembranei | 563 – 583 | Helical; Name=2Sequence analysisAdd BLAST | 21 | |
Topological domaini | 584 – 669 | CytoplasmicBy similarityAdd BLAST | 86 |
Keywords - Cellular componenti
Cell membrane, Cell projection, Cytoplasm, MembranePathology & Biotechi
Involvement in diseasei
Pseudohypoaldosteronism 1, autosomal recessive (PHA1B)3 Publications
The disease is caused by mutations affecting the gene represented in this entry. The degree of channel function impairment differentially affects the renin-aldosterone system and urinary Na/K ratios, resulting in distinct genotype-phenotype relationships in PHA1 patients. Loss-of-function mutations are associated with a severe clinical course and age-dependent hyperactivation of the renin-aldosterone system. This feature is not observed in patients with missense mutations that reduce but do not eliminate channel function. Markedly reduced channel activity results in impaired linear growth and delayed puberty (PubMed:18634878).1 Publication
Disease descriptionA rare salt wasting disease resulting from target organ unresponsiveness to mineralocorticoids. PHA1B is a severe form involving multiple organ systems, and characterized by an often fulminant presentation in the neonatal period with dehydration, hyponatremia, hyperkalemia, metabolic acidosis, failure to thrive and weight loss.
See also OMIM:264350Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_026518 | 327 | G → C in PHA1B; results in a significant reduction of channel function as compared to wild-type; significantly lowers both Li+ and Na+ ion currents. 2 PublicationsCorresponds to variant dbSNP:rs974854786Ensembl. | 1 | |
Natural variantiVAR_015834 | 562 | S → L in PHA1B. 1 PublicationCorresponds to variant dbSNP:rs137852635Ensembl. | 1 |
Bronchiectasis with or without elevated sweat chloride 2 (BESC2)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA debilitating respiratory disease characterized by chronic, abnormal dilatation of the bronchi and other cystic fibrosis-like symptoms in the absence of known causes of bronchiectasis (cystic fibrosis, autoimmune diseases, ciliary dyskinesia, common variable immunodeficiency, foreign body obstruction). Clinical features include sub-normal lung function, sinopulmonary infections, chronic productive cough, excessive sputum production, and elevated sweat chloride in some cases.
See also OMIM:613021Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_060793 | 61 | F → L in BESC2; hypoactive mutation resulting in reduction of protein expression and a significant decrease of amiloride-sensitive sodium currents. 1 PublicationCorresponds to variant dbSNP:rs61758859Ensembl. | 1 | |
Natural variantiVAR_060794 | 114 | V → I in BESC2; hyperactive mutation resulting in a significant increase of amiloride-sensitive sodium currents. 1 PublicationCorresponds to variant dbSNP:rs61759861Ensembl. | 1 |
Keywords - Diseasei
Disease mutationOrganism-specific databases
DisGeNETi | 6337. |
MalaCardsi | SCNN1A. |
MIMi | 264350. phenotype. 613021. phenotype. |
OpenTargetsi | ENSG00000111319. |
Orphaneti | 171876. Generalized pseudohypoaldosteronism type 1. 60033. Idiopathic bronchiectasis. |
PharmGKBi | PA305. |
Chemistry databases
ChEMBLi | CHEMBL1791. |
DrugBanki | DB00594. Amiloride. DB00384. Triamterene. |
GuidetoPHARMACOLOGYi | 738. |
Polymorphism and mutation databases
BioMutai | SCNN1A. |
DMDMi | 585966. |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000181261 | 1 – 669 | Amiloride-sensitive sodium channel subunit alphaAdd BLAST | 669 |
Post-translational modificationi
Ubiquitinated; this targets individual subunits for endocytosis and proteasome-mediated degradation.By similarity
ENaC cleavage by furin, and subsequently by prostasin (PRSS8), leads to a stepwise increase in the open probability of the channel as a result of release of the alpha and gamma subunit inhibitory tracts, respectively. Interaction of ENaC subunit SCNN1B with BPIFA1 protects ENaC against proteolytic activation.1 Publication
N-glycosylated.By similarity
Keywords - PTMi
Glycoprotein, Ubl conjugationProteomic databases
PaxDbi | P37088. |
PeptideAtlasi | P37088. |
PRIDEi | P37088. |
PTM databases
iPTMneti | P37088. |
PhosphoSitePlusi | P37088. |
Expressioni
Tissue specificityi
Expressed in the female reproductive tract, from the fimbrial end of the fallopian tube to the endometrium (at protein level) (PubMed:22207244). Expressed in kidney (at protein level). In the respiratory tract, expressed in the bronchial epithelium (at protein level). Highly expressed in lung. Detected at intermediate levels in pancreas and liver, and at low levels in heart and placenta (PubMed:22207244). in skin, expressed in keratinocytes, melanocytes and Merkel cells of the epidermal sub-layers, stratum basale, stratum spinosum and stratum granulosum (at protein level) (PubMed:28130590). Expressed in the outer root sheath of the hair follicles (at protein level) (PubMed:28130590). Detected in both peripheral and central cells of the sebaceous gland (at protein level) (PubMed:28130590). Expressed by eccrine sweat glands (at protein level) (PubMed:28130590). In skin, also expressed by arrector pili muscle cells and intradermal adipocytes (PubMed:28130590). Isoform 1 and isoform 2 predominate in all tissues. Expression of isoform 3, isoform 4 and isoform 5 is very low or not detectable, except in lung and heart (PubMed:9575806).3 Publications
Inductioni
By aldosterone.1 Publication
Gene expression databases
Bgeei | ENSG00000111319. |
CleanExi | HS_SCNN1A. |
ExpressionAtlasi | P37088. baseline and differential. |
Genevisiblei | P37088. HS. |
Organism-specific databases
HPAi | HPA012743. |
Interactioni
Subunit structurei
Heterotrimer containing an alpha/SCNN1A, a beta/SCNN1B and a gamma/SCNN1G subunit. An additional delta/SCNN1D subunit exists only in some organisms and can replace the alpha/SCNN1A subunit to form an alternative channel with specific properties (By similarity). Interacts with NEDD4 (via WW domains) (PubMed:11244092, PubMed:11696533, PubMed:12167593, PubMed:23665454). Interacts with NEDD4L (via WW domains) (PubMed:11244092, PubMed:11696533). Interacts with WWP1 (via WW domains) (PubMed:9169421). Interacts with WWP2 (via WW domains) (PubMed:12167593, PubMed:9169421). Interacts with the full-length immature form of PCSK9 (pro-PCSK9) (PubMed:22493497).By similarity6 Publications
Binary interactionsi
GO - Molecular functioni
- WW domain binding Source: BHF-UCL
Protein-protein interaction databases
BioGridi | 112241. 23 interactors. |
CORUMi | P37088. |
ELMi | P37088. |
IntActi | P37088. 4 interactors. |
MINTi | P37088. |
STRINGi | 9606.ENSP00000353292. |
Chemistry databases
BindingDBi | P37088. |
Structurei
Secondary structure
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more detailsFeature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Helixi | 644 – 647 | Combined sources | 4 |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
2M3O | NMR | - | P | 638-648 | [»] | |
ProteinModelPortali | P37088. | |||||
SMRi | P37088. | |||||
ModBasei | Search... | |||||
MobiDBi | Search... |
Family & Domainsi
Sequence similaritiesi
Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. SCNN1A subfamily. [View classification]Curated
Keywords - Domaini
Transmembrane, Transmembrane helixPhylogenomic databases
eggNOGi | KOG4294. Eukaryota. ENOG410ZNFK. LUCA. |
GeneTreei | ENSGT00760000119120. |
HOGENOMi | HOG000236286. |
HOVERGENi | HBG058435. |
InParanoidi | P37088. |
KOi | K04824. |
OMAi | VEYCDYR. |
OrthoDBi | EOG091G0KW6. |
PhylomeDBi | P37088. |
TreeFami | TF330663. |
Family and domain databases
InterProi | View protein in InterPro IPR001873. ENaC. IPR004724. ENaC_chordates. IPR020903. ENaC_CS. |
PANTHERi | PTHR11690. PTHR11690. 1 hit. |
Pfami | View protein in Pfam PF00858. ASC. 1 hit. |
PRINTSi | PR01078. AMINACHANNEL. |
TIGRFAMsi | TIGR00859. ENaC. 1 hit. |
PROSITEi | View protein in PROSITE PS01206. ASC. 1 hit. |
s (6)i Sequence
Sequence statusi: Complete.
This entry describes 6 produced by isoformsialternative splicing. AlignAdd to basket
Isoform 1 (identifier: P37088-1) [UniParc]FASTAAdd to basket
Also known as: Alpha ENAC1
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.
10 20 30 40 50
MEGNKLEEQD SSPPQSTPGL MKGNKREEQG LGPEPAAPQQ PTAEEEALIE
60 70 80 90 100
FHRSYRELFE FFCNNTTIHG AIRLVCSQHN RMKTAFWAVL WLCTFGMMYW
110 120 130 140 150
QFGLLFGEYF SYPVSLNINL NSDKLVFPAV TICTLNPYRY PEIKEELEEL
160 170 180 190 200
DRITEQTLFD LYKYSSFTTL VAGSRSRRDL RGTLPHPLQR LRVPPPPHGA
210 220 230 240 250
RRARSVASSL RDNNPQVDWK DWKIGFQLCN QNKSDCFYQT YSSGVDAVRE
260 270 280 290 300
WYRFHYINIL SRLPETLPSL EEDTLGNFIF ACRFNQVSCN QANYSHFHHP
310 320 330 340 350
MYGNCYTFND KNNSNLWMSS MPGINNGLSL MLRAEQNDFI PLLSTVTGAR
360 370 380 390 400
VMVHGQDEPA FMDDGGFNLR PGVETSISMR KETLDRLGGD YGDCTKNGSD
410 420 430 440 450
VPVENLYPSK YTQQVCIHSC FQESMIKECG CAYIFYPRPQ NVEYCDYRKH
460 470 480 490 500
SSWGYCYYKL QVDFSSDHLG CFTKCRKPCS VTSYQLSAGY SRWPSVTSQE
510 520 530 540 550
WVFQMLSRQN NYTVNNKRNG VAKVNIFFKE LNYKTNSESP SVTMVTLLSN
560 570 580 590 600
LGSQWSLWFG SSVLSVVEMA ELVFDLLVIM FLMLLRRFRS RYWSPGRGGR
610 620 630 640 650
GAQEVASTLA SSPPSHFCPH PMSLSLSQPG PAPSPALTAP PPAYATLGPR
660
PSPGGSAGAS SSTCPLGGP
Isoform 3 (identifier: P37088-3) [UniParc]FASTAAdd to basket
Also known as: Alpha ENACx
The sequence of this isoform differs from the canonical sequence as follows:
229-245: CNQNKSDCFYQTYSSGV → ELLSLPPPDVWKLLYFG
246-669: Missing.
Note: Does not give rise to amiloride-sensitive ion current. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
Show »Sequence cautioni
The sequence AAH06526 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated
Natural variant
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_060793 | 61 | F → L in BESC2; hypoactive mutation resulting in reduction of protein expression and a significant decrease of amiloride-sensitive sodium currents. 1 PublicationCorresponds to variant dbSNP:rs61758859Ensembl. | 1 | |
Natural variantiVAR_060794 | 114 | V → I in BESC2; hyperactive mutation resulting in a significant increase of amiloride-sensitive sodium currents. 1 PublicationCorresponds to variant dbSNP:rs61759861Ensembl. | 1 | |
Natural variantiVAR_060795 | 181 | R → W Functional polymorphism; significant increase of amiloride-sensitive sodium currents. 2 PublicationsCorresponds to variant dbSNP:rs55797039Ensembl. | 1 | |
Natural variantiVAR_026518 | 327 | G → C in PHA1B; results in a significant reduction of channel function as compared to wild-type; significantly lowers both Li+ and Na+ ion currents. 2 PublicationsCorresponds to variant dbSNP:rs974854786Ensembl. | 1 | |
Natural variantiVAR_060796 | 334 | A → T Functional polymorphism; significant decrease of amiloride-sensitive sodium currents. 2 PublicationsCorresponds to variant dbSNP:rs11542844Ensembl. | 1 | |
Natural variantiVAR_052035 | 402 | P → H. Corresponds to variant dbSNP:rs13306616Ensembl. | 1 | |
Natural variantiVAR_015833 | 493 | W → R Functional polymorphism; results in a 4-fold increase of amiloride-sensitive sodium currents; found in BESC2 patients at higher frequency than in controls; associated with an increased risk for ischemic cerebrovascular events. 2 PublicationsCorresponds to variant dbSNP:rs5742912Ensembl. | 1 | |
Natural variantiVAR_015834 | 562 | S → L in PHA1B. 1 PublicationCorresponds to variant dbSNP:rs137852635Ensembl. | 1 | |
Natural variantiVAR_060797 | 573 | V → I. Corresponds to variant dbSNP:rs59142484Ensembl. | 1 | |
Natural variantiVAR_022142 | 618 | C → F1 PublicationCorresponds to variant dbSNP:rs3741913Ensembl. | 1 | |
Natural variantiVAR_015835 | 663 | T → A7 PublicationsCorresponds to variant dbSNP:rs2228576Ensembl. | 1 |
Alternative sequence
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Alternative sequenceiVSP_007719 | 1 | M → MGMARGSLTRVPGVMGEGTQ GPELSLDPDPCSPQSTPGLM KGNKLEEQDPRPLQPIPGLM in isoform 2. Curated | 1 | |
Alternative sequenceiVSP_043667 | 1 | M → MSSIKGNKLEEQDPRPLQPI PGLM in isoform 6. 1 Publication | 1 | |
Alternative sequenceiVSP_007720 | 229 – 245 | CNQNK…YSSGV → ELLSLPPPDVWKLLYFG in isoform 3. CuratedAdd BLAST | 17 | |
Alternative sequenceiVSP_007721 | 246 – 669 | Missing in isoform 3. CuratedAdd BLAST | 424 | |
Alternative sequenceiVSP_007722 | 327 – 345 | Missing in isoform 4. CuratedAdd BLAST | 19 | |
Alternative sequenceiVSP_007723 | 454 | G → GQVRSLTPVIPALWEAEAGG SRG in isoform 5. Curated | 1 |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | X76180 mRNA. Translation: CAA53773.1. L29007 Genomic DNA. Translation: AAA21813.1. Z92978 Z92981 Genomic DNA. Translation: CAB07505.1. AF060913 AF060912 Genomic DNA. Translation: AAD28355.1. DQ402522 mRNA. Translation: ABD72218.1. AK304379 mRNA. Translation: BAG65217.1. FJ515830 Genomic DNA. Translation: ACS13721.1. AC005840 Genomic DNA. No translation available. AC006057 Genomic DNA. No translation available. CH471116 Genomic DNA. Translation: EAW88804.1. BC006526 mRNA. Translation: AAH06526.2. Different initiation. BC062613 mRNA. Translation: AAH62613.1. U81961 Genomic DNA. Translation: AAC31773.1. U81961 Genomic DNA. Translation: AAC31774.1. |
CCDSi | CCDS53738.1. [P37088-2] CCDS53739.1. [P37088-6] CCDS8543.1. [P37088-1] |
PIRi | A49585. |
RefSeqi | NP_001029.1. NM_001038.5. [P37088-1] NP_001153047.1. NM_001159575.1. [P37088-6] NP_001153048.1. NM_001159576.1. [P37088-2] |
UniGenei | Hs.591047. |
Genome annotation databases
Ensembli | ENST00000228916; ENSP00000228916; ENSG00000111319. [P37088-1] ENST00000360168; ENSP00000353292; ENSG00000111319. [P37088-2] ENST00000543768; ENSP00000438739; ENSG00000111319. [P37088-6] |
GeneIDi | 6337. |
KEGGi | hsa:6337. |
UCSCi | uc001qnw.3. human. [P37088-1] |
Keywords - Coding sequence diversityi
Alternative splicing, PolymorphismSimilar proteinsi
Entry informationi
Entry namei | SCNNA_HUMAN | |
Accessioni | P37088Primary (citable) accession number: P37088 Secondary accession number(s): A5X2U9 Q9UM64 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | October 1, 1994 |
Last sequence update: | October 1, 1994 | |
Last modified: | March 28, 2018 | |
This is version 189 of the entry and version 1 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program | |
Disclaimer | Any 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. |