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Q9Y3Q4 (HCN4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 124. 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·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4
Gene names
Name:HCN4
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1203 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Hyperpolarization-activated ion channel with very slow activation and inactivation exhibiting weak selectivity for potassium over sodium ions. Contributes to the native pacemaker currents in heart (If) that regulate the rhythm of heart beat. May contribute to the native pacemaker currents in neurons (Ih). May mediate responses to sour stimuli. Ref.1 Ref.2 Ref.3 Ref.4 Ref.8

Enzyme regulation

Activated by cAMP. cAMP binding causes a conformation change that leads to the assembly of an active tetramer and channel opening. Ref.4 Ref.5 Ref.8

Subunit structure

Homotetramer. The potassium channel is composed of a homo- or heterotetrameric complex of pore-forming subunits. Ref.4 Ref.5

Subcellular location

Cell membrane; Multi-pass membrane protein Ref.1 Ref.2 Ref.8.

Tissue specificity

Highly expressed in thalamus, testis and in heart, both in ventricle and atrium. Detected at much lower levels in amygdala, substantia nigra, cerebellum and hippocampus. Ref.1 Ref.2

Domain

The segment S4 is probably the voltage-sensor and is characterized by a series of positively charged amino acids at every third position.

Involvement in disease

Sick sinus syndrome 2 (SSS2) [MIM:163800]: The term 'sick sinus syndrome' encompasses a variety of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope, dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors. SSS2 onset is in utero or at birth.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.6 Ref.8 Ref.9

Brugada syndrome 8 (BRGDA8) [MIM:613123]: A tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.3

Miscellaneous

Inhibited by extracellular cesium ions.

Sequence similarities

Belongs to the potassium channel HCN family.

Contains 1 cyclic nucleotide-binding domain.

Ontologies

Keywords
   Biological processIon transport
Potassium transport
Sodium transport
Transport
   Cellular componentCell membrane
Membrane
   DiseaseBrugada syndrome
Disease mutation
   DomainTransmembrane
Transmembrane helix
   LigandcAMP
cAMP-binding
Nucleotide-binding
Potassium
Sodium
   Molecular functionIon channel
Ligand-gated ion channel
Potassium channel
Sodium channel
Voltage-gated channel
   PTMGlycoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processblood circulation

Non-traceable author statement Ref.1. Source: ProtInc

cation transport

Traceable author statement Ref.1. Source: ProtInc

cellular response to cAMP

Inferred from direct assay Ref.8. Source: UniProtKB

cellular response to cGMP

Inferred from direct assay PubMed 22748890. Source: UniProt

in utero embryonic development

Inferred from electronic annotation. Source: Ensembl

muscle contraction

Traceable author statement Ref.1. Source: ProtInc

potassium ion transmembrane transport

Inferred from direct assay Ref.8. Source: UniProtKB

regulation of heart rate

Inferred from mutant phenotype Ref.8. Source: UniProtKB

regulation of membrane potential

Inferred from mutant phenotype PubMed 22748890. Source: UniProt

sodium ion transmembrane transport

Inferred from mutant phenotype PubMed 22748890. Source: UniProt

synaptic transmission

Traceable author statement. Source: Reactome

   Cellular_componentintegral component of plasma membrane

Inferred from Biological aspect of Ancestor. Source: RefGenome

intrinsic component of plasma membrane

Inferred from direct assay Ref.8. Source: UniProtKB

plasma membrane

Inferred from direct assay PubMed 22748890. Source: UniProt

terminal bouton

Inferred from electronic annotation. Source: Ensembl

   Molecular_functioncAMP binding

Inferred from electronic annotation. Source: UniProtKB-KW

cation channel activity

Traceable author statement Ref.1. Source: ProtInc

identical protein binding

Inferred from physical interaction Ref.5. Source: IntAct

intracellular cAMP activated cation channel activity

Inferred from direct assay Ref.8. Source: UniProtKB

voltage-gated potassium channel activity

Inferred from direct assay Ref.8. Source: UniProtKB

voltage-gated sodium channel activity

Inferred from mutant phenotype PubMed 22748890. Source: UniProt

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

itself2EBI-1753521,EBI-1753521

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 12031203Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4
PRO_0000054117

Regions

Topological domain1 – 266266Cytoplasmic Potential
Transmembrane267 – 28721Helical; Name=Segment S1; Potential
Topological domain288 – 2936Extracellular Potential
Transmembrane294 – 31421Helical; Name=Segment S2; Potential
Topological domain315 – 34026Cytoplasmic Potential
Transmembrane341 – 36121Helical; Name=Segment S3; Potential
Topological domain362 – 3687Extracellular Potential
Transmembrane369 – 38921Helical; Voltage-sensor; Name=Segment S4; Potential
Topological domain390 – 42031Cytoplasmic Potential
Transmembrane421 – 44121Helical; Name=Segment S5; Potential
Topological domain442 – 46423Extracellular Potential
Intramembrane465 – 48622Pore-forming; Name=Segment H5; Potential
Topological domain487 – 49610Extracellular Potential
Transmembrane497 – 51721Helical; Name=Segment S6; Potential
Topological domain518 – 1203686Cytoplasmic Potential
Nucleotide binding659 – 6624cAMP
Nucleotide binding669 – 6702cAMP
Nucleotide binding710 – 7134cAMP
Region209 – 26052Involved in subunit assembly By similarity
Compositional bias924 – 1076153Pro-rich

Amino acid modifications

Glycosylation4581N-linked (GlcNAc...) Potential

Natural variations

Natural variant4851A → V in SSS2; results in a significant reduction of current density compared to wild-type. Ref.9
VAR_066614
Natural variant5531D → N in a patient with cardiac arrhythmia. Ref.7
VAR_026534
Natural variant6721S → R in SSS2; shifts the current activation range to hyperpolarized voltages, slows channel opening and speeds up channel closure, decreases affinity for cAMP, but does not abolish activation by cAMP. Ref.6 Ref.8
VAR_026535

Experimental info

Sequence conflict1101S → T in CAB52754. Ref.2

Secondary structure

..................................... 1203
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q9Y3Q4 [UniParc].

Last modified November 1, 1999. Version 1.
Checksum: 7EFDD2D69CF1F9D9

FASTA1,203129,042
        10         20         30         40         50         60 
MDKLPPSMRK RLYSLPQQVG AKAWIMDEEE DAEEEGAGGR QDPSRRSIRL RPLPSPSPSA 

        70         80         90        100        110        120 
AAGGTESRSS ALGAADSEGP ARGAGKSSTN GDCRRFRGSL ASLGSRGGGS GGTGSGSSHG 

       130        140        150        160        170        180 
HLHDSAEERR LIAEGDASPG EDRTPPGLAA EPERPGASAQ PAASPPPPQQ PPQPASASCE 

       190        200        210        220        230        240 
QPSVDTAIKV EGGAAAGDQI LPEAEVRLGQ AGFMQRQFGA MLQPGVNKFS LRMFGSQKAV 

       250        260        270        280        290        300 
EREQERVKSA GFWIIHPYSD FRFYWDLTML LLMVGNLIII PVGITFFKDE NTTPWIVFNV 

       310        320        330        340        350        360 
VSDTFFLIDL VLNFRTGIVV EDNTEIILDP QRIKMKYLKS WFMVDFISSI PVDYIFLIVE 

       370        380        390        400        410        420 
TRIDSEVYKT ARALRIVRFT KILSLLRLLR LSRLIRYIHQ WEEIFHMTYD LASAVVRIVN 

       430        440        450        460        470        480 
LIGMMLLLCH WDGCLQFLVP MLQDFPDDCW VSINNMVNNS WGKQYSYALF KAMSHMLCIG 

       490        500        510        520        530        540 
YGRQAPVGMS DVWLTMLSMI VGATCYAMFI GHATALIQSL DSSRRQYQEK YKQVEQYMSF 

       550        560        570        580        590        600 
HKLPPDTRQR IHDYYEHRYQ GKMFDEESIL GELSEPLREE IINFNCRKLV ASMPLFANAD 

       610        620        630        640        650        660 
PNFVTSMLTK LRFEVFQPGD YIIREGTIGK KMYFIQHGVV SVLTKGNKET KLADGSYFGE 

       670        680        690        700        710        720 
ICLLTRGRRT ASVRADTYCR LYSLSVDNFN EVLEEYPMMR RAFETVALDR LDRIGKKNSI 

       730        740        750        760        770        780 
LLHKVQHDLN SGVFNYQENE IIQQIVQHDR EMAHCAHRVQ AAASATPTPT PVIWTPLIQA 

       790        800        810        820        830        840 
PLQAAAATTS VAIALTHHPR LPAAIFRPPP GSGLGNLGAG QTPRHLKRLQ SLIPSALGSA 

       850        860        870        880        890        900 
SPASSPSQVD TPSSSSFHIQ QLAGFSAPAG LSPLLPSSSS SPPPGACGSP SAPTPSAGVA 

       910        920        930        940        950        960 
ATTIAGFGHF HKALGGSLSS SDSPLLTPLQ PGARSPQAAQ PSPAPPGARG GLGLPEHFLP 

       970        980        990       1000       1010       1020 
PPPSSRSPSS SPGQLGQPPG ELSLGLATGP LSTPETPPRQ PEPPSLVAGA SGGASPVGFT 

      1030       1040       1050       1060       1070       1080 
PRGGLSPPGH SPGPPRTFPS APPRASGSHG SLLLPPASSP PPPQVPQRRG TPPLTPGRLT 

      1090       1100       1110       1120       1130       1140 
QDLKLISASQ PALPQDGAQT LRRASPHSSG ESMAAFPLFP RAGGGSGGSG SSGGLGPPGR 

      1150       1160       1170       1180       1190       1200 
PYGAIPGQHV TLPRKTSSGS LPPPLSLFGA RATSSGGPPL TAGPQREPGA RPEPVRSKLP 


SNL 

« Hide

References

[1]"Two pacemaker channels from human heart with profoundly different activation kinetics."
Ludwig A., Zong X., Stieber J., Hullin R., Hofmann F., Biel M.
EMBO J. 18:2323-2329(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
Tissue: Heart.
[2]"Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis."
Seifert R., Scholten A., Gauss R., Mincheva A., Lichter P., Kaupp U.B.
Proc. Natl. Acad. Sci. U.S.A. 96:9391-9396(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
Tissue: Thalamus.
[3]"Role of HCN4 channel in preventing ventricular arrhythmia."
Ueda K., Hirano Y., Higashiuesato Y., Aizawa Y., Hayashi T., Inagaki N., Tana T., Ohya Y., Takishita S., Muratani H., Hiraoka M., Kimura A.
J. Hum. Genet. 54:115-121(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INVOLVEMENT IN BRGDA8.
[4]"Structural basis for the cAMP-dependent gating in the human HCN4 channel."
Xu X., Vysotskaya Z.V., Liu Q., Zhou L.
J. Biol. Chem. 285:37082-37091(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 521-739 IN COMPLEX WITH CAMP, NUCLEOTIDE-BINDING, FUNCTION, ENZYME REGULATION, SUBUNIT.
[5]"Tetramerization dynamics of C-terminal domain underlies isoform-specific cAMP gating in hyperpolarization-activated cyclic nucleotide-gated channels."
Lolicato M., Nardini M., Gazzarrini S., Moller S., Bertinetti D., Herberg F.W., Bolognesi M., Martin H., Fasolini M., Bertrand J.A., Arrigoni C., Thiel G., Moroni A.
J. Biol. Chem. 286:44811-44820(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 521-723 IN COMPLEX WITH CAMP, NUCLEOTIDE-BINDING, ENZYME REGULATION, SUBUNIT.
[6]"Local and global interpretations of a disease-causing mutation near the ligand entry path in hyperpolarization-activated cAMP-gated channel."
Xu X., Marni F., Wu S., Su Z., Musayev F., Shrestha S., Xie C., Gao W., Liu Q., Zhou L.
Structure 20:2116-2123(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 521-724, CHARACTERIZATION OF VARIANT SSS2 ARG-672.
[7]"Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia."
Ueda K., Nakamura K., Hayashi T., Inagaki N., Takahashi M., Arimura T., Morita H., Higashiuesato Y., Hirano Y., Yasunami M., Takishita S., Yamashina A., Ohe T., Sunamori M., Hiraoka M., Kimura A.
J. Biol. Chem. 279:27194-27198(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT CARDIAC ARRHYTHMIA ASN-553.
[8]"Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel."
Milanesi R., Baruscotti M., Gnecchi-Ruscone T., DiFrancesco D.
N. Engl. J. Med. 354:151-157(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT SSS2 ARG-672, FUNCTION, ENZYME REGULATION, SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANT SSS2 ARG-672.
[9]"A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in Moroccan Jews."
Laish-Farkash A., Glikson M., Brass D., Marek-Yagel D., Pras E., Dascal N., Antzelevitch C., Nof E., Reznik H., Eldar M., Luria D.
J. Cardiovasc. Electrophysiol. 21:1365-1372(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT SSS2 VAL-485, CHARACTERIZATION OF VARIANT SSS2 VAL-485.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AJ132429 mRNA. Translation: CAB42604.1.
AJ238850 mRNA. Translation: CAB52754.1.
CCDSCCDS10248.1.
RefSeqNP_005468.1. NM_005477.2.
UniGeneHs.86941.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
3OTFX-ray2.40A521-739[»]
3U11X-ray2.50A/B521-723[»]
4HBNX-ray2.60A521-724[»]
4KL1X-ray2.70A/B/C/D521-713[»]
4NVPX-ray2.50A521-723[»]
ProteinModelPortalQ9Y3Q4.
SMRQ9Y3Q4. Positions 463-717.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid115338. 3 interactions.
IntActQ9Y3Q4. 2 interactions.
STRING9606.ENSP00000261917.

Chemistry

BindingDBQ9Y3Q4.
ChEMBLCHEMBL1250417.
GuidetoPHARMACOLOGY403.

Protein family/group databases

TCDB1.A.1.5.10. the voltage-gated ion channel (vic) superfamily.
1.A.1.5.11. the voltage-gated ion channel (vic) superfamily.

PTM databases

PhosphoSiteQ9Y3Q4.

Polymorphism databases

DMDM38605641.

Proteomic databases

PaxDbQ9Y3Q4.
PRIDEQ9Y3Q4.

Protocols and materials databases

DNASU10021.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000261917; ENSP00000261917; ENSG00000138622.
GeneID10021.
KEGGhsa:10021.
UCSCuc002avp.3. human.

Organism-specific databases

CTD10021.
GeneCardsGC15M073612.
GeneReviewsHCN4.
HGNCHGNC:16882. HCN4.
MIM163800. phenotype.
605206. gene.
613123. phenotype.
neXtProtNX_Q9Y3Q4.
Orphanet130. Brugada syndrome.
166282. Familial sick sinus syndrome.
PharmGKBPA394.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0664.
HOGENOMHOG000230717.
HOVERGENHBG039490.
InParanoidQ9Y3Q4.
KOK04957.
OMAGFGHFHK.
OrthoDBEOG7VMP6X.
PhylomeDBQ9Y3Q4.
TreeFamTF318250.

Enzyme and pathway databases

ReactomeREACT_13685. Neuronal System.

Gene expression databases

BgeeQ9Y3Q4.
CleanExHS_HCN4.
GenevestigatorQ9Y3Q4.

Family and domain databases

Gene3D2.60.120.10. 1 hit.
InterProIPR018490. cNMP-bd-like.
IPR018488. cNMP-bd_CS.
IPR000595. cNMP-bd_dom.
IPR005821. Ion_trans_dom.
IPR013621. Ion_trans_N.
IPR003938. K_chnl_volt-dep_EAG/ELK/ERG.
IPR014710. RmlC-like_jellyroll.
[Graphical view]
PfamPF00027. cNMP_binding. 1 hit.
PF00520. Ion_trans. 1 hit.
PF08412. Ion_trans_N. 1 hit.
[Graphical view]
PRINTSPR01463. EAGCHANLFMLY.
SMARTSM00100. cNMP. 1 hit.
[Graphical view]
SUPFAMSSF51206. SSF51206. 1 hit.
PROSITEPS00888. CNMP_BINDING_1. 1 hit.
PS50042. CNMP_BINDING_3. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ9Y3Q4.
GeneWikiHCN4.
GenomeRNAi10021.
NextBio37865.
PROQ9Y3Q4.
SOURCESearch...

Entry information

Entry nameHCN4_HUMAN
AccessionPrimary (citable) accession number: Q9Y3Q4
Secondary accession number(s): Q9UMQ7
Entry history
Integrated into UniProtKB/Swiss-Prot: February 28, 2003
Last sequence update: November 1, 1999
Last modified: July 9, 2014
This is version 124 of the entry and version 1 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 15

Human chromosome 15: entries, gene names and cross-references to MIM