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Q9UL51

- HCN2_HUMAN

UniProt

Q9UL51 - HCN2_HUMAN

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Protein

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2

Gene

HCN2

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

Functioni

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.By similarity

Enzyme regulationi

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.2 Publications

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi608 – 6114cAMP1 Publication
Nucleotide bindingi618 – 6192cAMP1 Publication
Nucleotide bindingi659 – 6624cAMP1 Publication

GO - Molecular functioni

  1. cAMP binding Source: UniProtKB-KW
  2. identical protein binding Source: IntAct
  3. intracellular cAMP activated cation channel activity Source: UniProtKB
  4. voltage-gated potassium channel activity Source: UniProtKB
  5. voltage-gated sodium channel activity Source: UniProt

GO - Biological processi

  1. cell-cell signaling Source: ProtInc
  2. cellular response to cAMP Source: UniProtKB
  3. cellular response to cGMP Source: UniProt
  4. potassium ion transmembrane transport Source: UniProtKB
  5. regulation of membrane potential Source: UniProt
  6. sodium ion transmembrane transport Source: UniProt
  7. synaptic transmission Source: Reactome
Complete GO annotation...

Keywords - Molecular functioni

Ion channel, Ligand-gated ion channel, Potassium channel, Sodium channel, Voltage-gated channel

Keywords - Biological processi

Ion transport, Potassium transport, Sodium transport, Transport

Keywords - Ligandi

cAMP, cAMP-binding, Nucleotide-binding, Potassium, Sodium

Enzyme and pathway databases

ReactomeiREACT_75862. HCN channels.

Protein family/group databases

TCDBi1.A.1.5.11. the voltage-gated ion channel (vic) superfamily.

Names & Taxonomyi

Protein namesi
Recommended name:
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2
Alternative name(s):
Brain cyclic nucleotide-gated channel 2
Short name:
BCNG-2
Gene namesi
Name:HCN2
Synonyms:BCNG2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 19

Organism-specific databases

HGNCiHGNC:4846. HCN2.

Subcellular locationi

Cell membrane 2 Publications; Multi-pass membrane protein 2 Publications

GO - Cellular componenti

  1. integral component of plasma membrane Source: UniProtKB
  2. plasma membrane Source: UniProt
  3. voltage-gated potassium channel complex Source: ProtInc
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA78.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 889889Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2PRO_0000054111Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi407 – 4071N-linked (GlcNAc...)Sequence Analysis
Modified residuei668 – 6681Phosphoserine; by PKG/PRKG2By similarity

Post-translational modificationi

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

Keywords - PTMi

Glycoprotein, Phosphoprotein

Proteomic databases

PaxDbiQ9UL51.
PRIDEiQ9UL51.

PTM databases

PhosphoSiteiQ9UL51.

Expressioni

Tissue specificityi

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

Gene expression databases

BgeeiQ9UL51.
CleanExiHS_HCN2.
ExpressionAtlasiQ9UL51. baseline and differential.
GenevestigatoriQ9UL51.

Interactioni

Subunit structurei

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.By similarity1 Publication

Binary interactionsi

WithEntry#Exp.IntActNotes
itself2EBI-1751885,EBI-1751885

Protein-protein interaction databases

BioGridi107081. 4 interactions.
IntActiQ9UL51. 4 interactions.
STRINGi9606.ENSP00000251287.

Structurei

Secondary structure

1
889
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi471 – 48919Combined sources
Helixi494 – 50815Combined sources
Helixi515 – 5206Combined sources
Helixi524 – 53411Combined sources
Helixi536 – 5405Combined sources
Turni543 – 5475Combined sources
Helixi550 – 5578Combined sources
Beta strandi561 – 5655Combined sources
Beta strandi570 – 5723Combined sources
Beta strandi580 – 5867Combined sources
Beta strandi589 – 5924Combined sources
Beta strandi598 – 6014Combined sources
Beta strandi606 – 6083Combined sources
Helixi610 – 6145Combined sources
Beta strandi619 – 6268Combined sources
Beta strandi628 – 6347Combined sources
Helixi635 – 64410Combined sources
Helixi646 – 66116Combined sources
Turni662 – 6643Combined sources
Helixi668 – 6703Combined sources

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2MPFNMR-A521-672[»]
3U10X-ray2.30A470-672[»]
ProteinModelPortaliQ9UL51.
SMRiQ9UL51. Positions 412-662.
ModBaseiSearch...
MobiDBiSearch...

Topological domain

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 215215CytoplasmicSequence AnalysisAdd
BLAST
Topological domaini237 – 2404ExtracellularSequence Analysis
Topological domaini262 – 28827CytoplasmicSequence AnalysisAdd
BLAST
Topological domaini310 – 3178ExtracellularSequence Analysis
Topological domaini339 – 36931CytoplasmicSequence AnalysisAdd
BLAST
Topological domaini391 – 41323ExtracellularSequence AnalysisAdd
BLAST
Topological domaini436 – 4405ExtracellularSequence Analysis
Topological domaini462 – 889428CytoplasmicSequence AnalysisAdd
BLAST

Intramembrane

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Intramembranei414 – 43522Pore-forming; Name=Segment H5Sequence AnalysisAdd
BLAST

Transmembrane

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Transmembranei216 – 23621Helical; Name=Segment S1Sequence AnalysisAdd
BLAST
Transmembranei241 – 26121Helical; Name=Segment S2Sequence AnalysisAdd
BLAST
Transmembranei289 – 30921Helical; Name=Segment S3Sequence AnalysisAdd
BLAST
Transmembranei318 – 33821Helical; Voltage-sensor; Name=Segment S4Sequence AnalysisAdd
BLAST
Transmembranei370 – 39021Helical; Name=Segment S5Sequence AnalysisAdd
BLAST
Transmembranei441 – 46121Helical; Name=Segment S6Sequence AnalysisAdd
BLAST

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni158 – 20952Involved in subunit assemblyBy similarityAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi10 – 140131Pro-richAdd
BLAST
Compositional biasi715 – 861147Pro-richAdd
BLAST

Domaini

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

Sequence similaritiesi

Belongs to the potassium channel HCN family.Curated
Contains 1 cyclic nucleotide-binding domain.PROSITE-ProRule annotation

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiCOG0664.
GeneTreeiENSGT00760000118772.
HOGENOMiHOG000230717.
HOVERGENiHBG039489.
InParanoidiQ9UL51.
KOiK04955.
OMAiMRICNIS.
OrthoDBiEOG7VMP6X.
PhylomeDBiQ9UL51.
TreeFamiTF318250.

Family and domain databases

Gene3Di2.60.120.10. 1 hit.
InterProiIPR018490. 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]
PfamiPF00027. cNMP_binding. 1 hit.
PF00520. Ion_trans. 1 hit.
PF08412. Ion_trans_N. 1 hit.
[Graphical view]
PRINTSiPR01463. EAGCHANLFMLY.
SMARTiSM00100. cNMP. 1 hit.
[Graphical view]
SUPFAMiSSF51206. SSF51206. 1 hit.
PROSITEiPS00888. CNMP_BINDING_1. 1 hit.
PS50042. CNMP_BINDING_3. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q9UL51-1 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MDARGGGGRP GESPGATPAP GPPPPPPPAP PQQQPPPPPP PAPPPGPGPA
60 70 80 90 100
PPQHPPRAEA LPPEAADEGG PRGRLRSRDS SCGRPGTPGA ASTAKGSPNG
110 120 130 140 150
ECGRGEPQCS PAGPEGPARG PKVSFSCRGA ASGPAPGPGP AEEAGSEEAG
160 170 180 190 200
PAGEPRGSQA SFMQRQFGAL LQPGVNKFSL RMFGSQKAVE REQERVKSAG
210 220 230 240 250
AWIIHPYSDF RFYWDFTMLL FMVGNLIIIP VGITFFKDET TAPWIVFNVV
260 270 280 290 300
SDTFFLMDLV LNFRTGIVIE DNTEIILDPE KIKKKYLRTW FVVDFVSSIP
310 320 330 340 350
VDYIFLIVEK GIDSEVYKTA RALRIVRFTK ILSLLRLLRL SRLIRYIHQW
360 370 380 390 400
EEIFHMTYDL ASAVMRICNL ISMMLLLCHW DGCLQFLVPM LQDFPRNCWV
410 420 430 440 450
SINGMVNHSW SELYSFALFK AMSHMLCIGY GRQAPESMTD IWLTMLSMIV
460 470 480 490 500
GATCYAMFIG HATALIQSLD SSRRQYQEKY KQVEQYMSFH KLPADFRQKI
510 520 530 540 550
HDYYEHRYQG KMFDEDSILG ELNGPLREEI VNFNCRKLVA SMPLFANADP
560 570 580 590 600
NFVTAMLTKL KFEVFQPGDY IIREGTIGKK MYFIQHGVVS VLTKGNKEMK
610 620 630 640 650
LSDGSYFGEI CLLTRGRRTA SVRADTYCRL YSLSVDNFNE VLEEYPMMRR
660 670 680 690 700
AFETVAIDRL DRIGKKNSIL LHKVQHDLNS GVFNNQENAI IQEIVKYDRE
710 720 730 740 750
MVQQAELGQR VGLFPPPPPP PQVTSAIATL QQAAAMSFCP QVARPLVGPL
760 770 780 790 800
ALGSPRLVRR PPPGPAPAAA SPGPPPPASP PGAPASPRAP RTSPYGGLPA
810 820 830 840 850
APLAGPALPA RRLSRASRPL SASQPSLPHG APGPAASTRP ASSSTPRLGP
860 870 880
TPAARAAAPS PDRRDSASPG AAGGLDPQDS ARSRLSSNL
Length:889
Mass (Da):96,950
Last modified:June 13, 2006 - v3
Checksum:i4B263E0C06C2A47D
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti17 – 204TPAP → SPTT in AAC28444. (PubMed:10524219)Curated
Sequence conflicti29 – 291A → R in AAC28444. (PubMed:10524219)Curated
Sequence conflicti32 – 321Q → K in AAC28444. (PubMed:10524219)Curated
Sequence conflicti294 – 2941D → V in AAC39760. (PubMed:9630217)Curated
Sequence conflicti713 – 7131L → F in AAC39760. (PubMed:9630217)Curated
Sequence conflicti849 – 8491G → R in CAB42602. (PubMed:10228147)Curated
Sequence conflicti849 – 8491G → R in CAB42630. (PubMed:10228147)Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti527 – 5271R → Q.
Corresponds to variant rs55687900 [ dbSNP | Ensembl ].
VAR_061106

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AF065164 mRNA. Translation: AAC28444.2.
AJ012582 mRNA. Translation: CAB42602.1.
AJ133727
, 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.
CCDSiCCDS12035.1.
RefSeqiNP_001185.3. NM_001194.3.
UniGeneiHs.124161.

Genome annotation databases

GeneIDi610.
KEGGihsa:610.
UCSCiuc002lpe.3. human.

Polymorphism databases

DMDMi108935843.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AF065164 mRNA. Translation: AAC28444.2 .
AJ012582 mRNA. Translation: CAB42602.1 .
AJ133727
, 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 .
CCDSi CCDS12035.1.
RefSeqi NP_001185.3. NM_001194.3.
UniGenei Hs.124161.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
2MPF NMR - A 521-672 [» ]
3U10 X-ray 2.30 A 470-672 [» ]
ProteinModelPortali Q9UL51.
SMRi Q9UL51. Positions 412-662.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 107081. 4 interactions.
IntActi Q9UL51. 4 interactions.
STRINGi 9606.ENSP00000251287.

Chemistry

ChEMBLi CHEMBL1795172.
GuidetoPHARMACOLOGYi 401.

Protein family/group databases

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

PTM databases

PhosphoSitei Q9UL51.

Polymorphism databases

DMDMi 108935843.

Proteomic databases

PaxDbi Q9UL51.
PRIDEi Q9UL51.

Protocols and materials databases

DNASUi 610.
Structural Biology Knowledgebase Search...

Genome annotation databases

GeneIDi 610.
KEGGi hsa:610.
UCSCi uc002lpe.3. human.

Organism-specific databases

CTDi 610.
GeneCardsi GC19P000589.
HGNCi HGNC:4846. HCN2.
MIMi 602781. gene.
neXtProti NX_Q9UL51.
PharmGKBi PA78.
GenAtlasi Search...

Phylogenomic databases

eggNOGi COG0664.
GeneTreei ENSGT00760000118772.
HOGENOMi HOG000230717.
HOVERGENi HBG039489.
InParanoidi Q9UL51.
KOi K04955.
OMAi MRICNIS.
OrthoDBi EOG7VMP6X.
PhylomeDBi Q9UL51.
TreeFami TF318250.

Enzyme and pathway databases

Reactomei REACT_75862. HCN channels.

Miscellaneous databases

GeneWikii HCN2.
GenomeRNAii 610.
NextBioi 2477.
PROi Q9UL51.
SOURCEi Search...

Gene expression databases

Bgeei Q9UL51.
CleanExi HS_HCN2.
ExpressionAtlasi Q9UL51. baseline and differential.
Genevestigatori Q9UL51.

Family and domain databases

Gene3Di 2.60.120.10. 1 hit.
InterProi IPR018490. 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 ]
Pfami PF00027. cNMP_binding. 1 hit.
PF00520. Ion_trans. 1 hit.
PF08412. Ion_trans_N. 1 hit.
[Graphical view ]
PRINTSi PR01463. EAGCHANLFMLY.
SMARTi SM00100. cNMP. 1 hit.
[Graphical view ]
SUPFAMi SSF51206. SSF51206. 1 hit.
PROSITEi PS00888. CNMP_BINDING_1. 1 hit.
PS50042. CNMP_BINDING_3. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. 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.
    , 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. 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.

Entry informationi

Entry nameiHCN2_HUMAN
AccessioniPrimary (citable) accession number: Q9UL51
Secondary accession number(s): O60742
, O60743, O75267, Q9UBS2
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 28, 2003
Last sequence update: June 13, 2006
Last modified: October 29, 2014
This is version 124 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Miscellaneous

Inhibited by extracellular cesium ions.

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 19
    Human chromosome 19: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3