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Q9UL51 (HCN2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 121. 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 2
Alternative name(s):
Brain cyclic nucleotide-gated channel 2
Short name=BCNG-2
Gene names
Name:HCN2
Synonyms:BCNG2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length889 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Hyperpolarization-activated ion channel exhibiting weak selectivity for potassium over sodium ions. Contributes to the native pacemaker currents in heart (If) and in neurons (Ih). Can also transport ammonium in the distal nephron. Produces a large instantaneous current. Modulated by intracellular chloride ions and pH; acidic pH shifts the activation to more negative voltages By similarity. Ref.1 Ref.2

Enzyme regulation

Activated by cAMP, and at 10-100 times higher concentrations, also by cGMP. cAMP binding causes a conformation change that leads to the assembly of an active tetramer and channel opening. Channel activity is modulated by intracellular chloride ions and pH; acidic pH shifts the activation to more negative voltages. Ref.2 Ref.6

Subunit structure

The potassium channel is composed of a homo- or heterotetrameric complex of pore-forming subunits. Heterotetramer with HCN1. Forms an obligate 4:4 complex with accessory subunit PEX5L. Interacts with KCNE2 By similarity. Homotetramer. Ref.6

Subcellular location

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

Tissue specificity

Highly expressed throughout the brain. Detected at low levels in heart. Ref.2 Ref.4

Domain

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

Post-translational modification

Phosphorylation at Ser-668 by PRKG2 shifts the voltage-dependence to more negative voltages, hence counteracting the stimulatory effect of cGMP on gating By similarity.

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
   Coding sequence diversityPolymorphism
   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
Phosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcell-cell signaling

Traceable author statement Ref.4. Source: ProtInc

cellular response to cAMP

Inferred from direct assay Ref.2. Source: UniProtKB

cellular response to cGMP

Inferred from direct assay PubMed 22748890. Source: UniProt

potassium ion transmembrane transport

Inferred from direct assay Ref.2. 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 direct assay Ref.2. Source: UniProtKB

plasma membrane

Inferred from direct assay PubMed 22748890. Source: UniProt

voltage-gated potassium channel complex

Traceable author statement Ref.4. Source: ProtInc

   Molecular_functioncAMP binding

Inferred from electronic annotation. Source: UniProtKB-KW

identical protein binding

Inferred from physical interaction Ref.6. Source: IntAct

intracellular cAMP activated cation channel activity

Inferred from direct assay Ref.2. Source: UniProtKB

voltage-gated potassium channel activity

Inferred from direct assay Ref.2. 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-1751885,EBI-1751885

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 889889Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2
PRO_0000054111

Regions

Topological domain1 – 215215Cytoplasmic Potential
Transmembrane216 – 23621Helical; Name=Segment S1; Potential
Topological domain237 – 2404Extracellular Potential
Transmembrane241 – 26121Helical; Name=Segment S2; Potential
Topological domain262 – 28827Cytoplasmic Potential
Transmembrane289 – 30921Helical; Name=Segment S3; Potential
Topological domain310 – 3178Extracellular Potential
Transmembrane318 – 33821Helical; Voltage-sensor; Name=Segment S4; Potential
Topological domain339 – 36931Cytoplasmic Potential
Transmembrane370 – 39021Helical; Name=Segment S5; Potential
Topological domain391 – 41323Extracellular Potential
Intramembrane414 – 43522Pore-forming; Name=Segment H5; Potential
Topological domain436 – 4405Extracellular Potential
Transmembrane441 – 46121Helical; Name=Segment S6; Potential
Topological domain462 – 889428Cytoplasmic Potential
Nucleotide binding608 – 6114cAMP
Nucleotide binding618 – 6192cAMP
Nucleotide binding659 – 6624cAMP
Region158 – 20952Involved in subunit assembly By similarity
Compositional bias10 – 140131Pro-rich
Compositional bias715 – 861147Pro-rich

Amino acid modifications

Modified residue6681Phosphoserine; by PKG/PRKG2 By similarity
Glycosylation4071N-linked (GlcNAc...) Potential

Natural variations

Natural variant5271R → Q.
Corresponds to variant rs55687900 [ dbSNP | Ensembl ].
VAR_061106

Experimental info

Sequence conflict17 – 204TPAP → SPTT in AAC28444. Ref.1
Sequence conflict291A → R in AAC28444. Ref.1
Sequence conflict321Q → K in AAC28444. Ref.1
Sequence conflict2941D → V in AAC39760. Ref.4
Sequence conflict7131L → F in AAC39760. Ref.4
Sequence conflict8491G → R in CAB42602. Ref.2
Sequence conflict8491G → R in CAB42630. Ref.2

Secondary structure

....................................... 889
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q9UL51 [UniParc].

Last modified June 13, 2006. Version 3.
Checksum: 4B263E0C06C2A47D

FASTA88996,950
        10         20         30         40         50         60 
MDARGGGGRP GESPGATPAP GPPPPPPPAP PQQQPPPPPP PAPPPGPGPA PPQHPPRAEA 

        70         80         90        100        110        120 
LPPEAADEGG PRGRLRSRDS SCGRPGTPGA ASTAKGSPNG ECGRGEPQCS PAGPEGPARG 

       130        140        150        160        170        180 
PKVSFSCRGA ASGPAPGPGP AEEAGSEEAG PAGEPRGSQA SFMQRQFGAL LQPGVNKFSL 

       190        200        210        220        230        240 
RMFGSQKAVE REQERVKSAG AWIIHPYSDF RFYWDFTMLL FMVGNLIIIP VGITFFKDET 

       250        260        270        280        290        300 
TAPWIVFNVV SDTFFLMDLV LNFRTGIVIE DNTEIILDPE KIKKKYLRTW FVVDFVSSIP 

       310        320        330        340        350        360 
VDYIFLIVEK GIDSEVYKTA RALRIVRFTK ILSLLRLLRL SRLIRYIHQW EEIFHMTYDL 

       370        380        390        400        410        420 
ASAVMRICNL ISMMLLLCHW DGCLQFLVPM LQDFPRNCWV SINGMVNHSW SELYSFALFK 

       430        440        450        460        470        480 
AMSHMLCIGY GRQAPESMTD IWLTMLSMIV GATCYAMFIG HATALIQSLD SSRRQYQEKY 

       490        500        510        520        530        540 
KQVEQYMSFH KLPADFRQKI HDYYEHRYQG KMFDEDSILG ELNGPLREEI VNFNCRKLVA 

       550        560        570        580        590        600 
SMPLFANADP NFVTAMLTKL KFEVFQPGDY IIREGTIGKK MYFIQHGVVS VLTKGNKEMK 

       610        620        630        640        650        660 
LSDGSYFGEI CLLTRGRRTA SVRADTYCRL YSLSVDNFNE VLEEYPMMRR AFETVAIDRL 

       670        680        690        700        710        720 
DRIGKKNSIL LHKVQHDLNS GVFNNQENAI IQEIVKYDRE MVQQAELGQR VGLFPPPPPP 

       730        740        750        760        770        780 
PQVTSAIATL QQAAAMSFCP QVARPLVGPL ALGSPRLVRR PPPGPAPAAA SPGPPPPASP 

       790        800        810        820        830        840 
PGAPASPRAP RTSPYGGLPA APLAGPALPA RRLSRASRPL SASQPSLPHG APGPAASTRP 

       850        860        870        880 
ASSSTPRLGP TPAARAAAPS PDRRDSASPG AAGGLDPQDS ARSRLSSNL 

« Hide

References

« Hide 'large scale' references
[1]"The human gene coding for HCN2, a pacemaker channel of the heart."
Vaccari T., Moroni A., Rocchi M., Gorza L., Bianchi M.E., Beltrame M., DiFrancesco D.
Biochim. Biophys. Acta 1446:419-425(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION.
[2]"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 [GENOMIC DNA / MRNA], FUNCTION, ENZYME REGULATION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
Tissue: Heart.
[3]"The DNA sequence and biology of human chromosome 19."
Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., Carrano A.V. expand/collapse author list , Caoile C., Chan Y.M., Christensen M., Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., Rubin E.M., Lucas S.M.
Nature 428:529-535(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]"Identification of a gene encoding a hyperpolarization-activated 'pacemaker' channel of brain."
Santoro B., Liu D.T., Yao H., Bartsch D., Kandel E.R., Siegelbaum S.A., Tibbs G.R.
Cell 93:717-729(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 147-743, TISSUE SPECIFICITY.
Tissue: Brain.
[5]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[6]"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 (2.3 ANGSTROMS) OF 470-672 IN COMPLEX WITH CAMP, NUCLEOTIDE-BINDING, ENZYME REGULATION, SUBUNIT.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF065164 mRNA. Translation: AAC28444.2.
AJ012582 mRNA. Translation: CAB42602.1.
AJ133727 expand/collapse EMBL AC list , AJ133728, AJ133729, AJ133730, AJ133731, AJ133732, AJ133733, AJ133734 Genomic DNA. Translation: CAB42630.1.
AC004449 Genomic DNA. No translation available.
AC005559 Genomic DNA. Translation: AAC33280.2.
AF064877 mRNA. Translation: AAC39760.1.
CCDSCCDS12035.1.
RefSeqNP_001185.3. NM_001194.3.
UniGeneHs.124161.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
3U10X-ray2.30A470-672[»]
ProteinModelPortalQ9UL51.
SMRQ9UL51. Positions 412-662.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid107081. 4 interactions.
IntActQ9UL51. 4 interactions.
STRING9606.ENSP00000251287.

Chemistry

ChEMBLCHEMBL1795172.
GuidetoPHARMACOLOGY401.

Protein family/group databases

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

PTM databases

PhosphoSiteQ9UL51.

Polymorphism databases

DMDM108935843.

Proteomic databases

PaxDbQ9UL51.
PRIDEQ9UL51.

Protocols and materials databases

DNASU610.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000251287; ENSP00000251287; ENSG00000099822.
GeneID610.
KEGGhsa:610.
UCSCuc002lpe.3. human.

Organism-specific databases

CTD610.
GeneCardsGC19P000589.
HGNCHGNC:4846. HCN2.
MIM602781. gene.
neXtProtNX_Q9UL51.
PharmGKBPA78.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0664.
HOGENOMHOG000230717.
HOVERGENHBG039489.
InParanoidQ9UL51.
KOK04955.
OMAMRICNIS.
OrthoDBEOG7VMP6X.
PhylomeDBQ9UL51.
TreeFamTF318250.

Enzyme and pathway databases

ReactomeREACT_13685. Neuronal System.

Gene expression databases

ArrayExpressQ9UL51.
BgeeQ9UL51.
CleanExHS_HCN2.
GenevestigatorQ9UL51.

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

GeneWikiHCN2.
GenomeRNAi610.
NextBio2477.
PROQ9UL51.
SOURCESearch...

Entry information

Entry nameHCN2_HUMAN
AccessionPrimary (citable) accession number: Q9UL51
Secondary accession number(s): O60742 expand/collapse secondary AC list , O60743, O75267, Q9UBS2
Entry history
Integrated into UniProtKB/Swiss-Prot: February 28, 2003
Last sequence update: June 13, 2006
Last modified: July 9, 2014
This is version 121 of the entry and version 3 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 19

Human chromosome 19: entries, gene names and cross-references to MIM