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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, BCNG2
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.2 Publications

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 – 6114cAMP
Nucleotide bindingi618 – 6192cAMP
Nucleotide bindingi659 – 6624cAMP

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; Multi-pass membrane protein 2 Publications

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 215215Cytoplasmic Reviewed prediction
Add
BLAST
Transmembranei216 – 23621Helical; Name=Segment S1; Reviewed prediction
Add
BLAST
Topological domaini237 – 2404Extracellular Reviewed prediction
Transmembranei241 – 26121Helical; Name=Segment S2; Reviewed prediction
Add
BLAST
Topological domaini262 – 28827Cytoplasmic Reviewed prediction
Add
BLAST
Transmembranei289 – 30921Helical; Name=Segment S3; Reviewed prediction
Add
BLAST
Topological domaini310 – 3178Extracellular Reviewed prediction
Transmembranei318 – 33821Helical; Voltage-sensor; Name=Segment S4; Reviewed prediction
Add
BLAST
Topological domaini339 – 36931Cytoplasmic Reviewed prediction
Add
BLAST
Transmembranei370 – 39021Helical; Name=Segment S5; Reviewed prediction
Add
BLAST
Topological domaini391 – 41323Extracellular Reviewed prediction
Add
BLAST
Intramembranei414 – 43522Pore-forming; Name=Segment H5; Reviewed prediction
Add
BLAST
Topological domaini436 – 4405Extracellular Reviewed prediction
Transmembranei441 – 46121Helical; Name=Segment S6; Reviewed prediction
Add
BLAST
Topological domaini462 – 889428Cytoplasmic Reviewed prediction
Add
BLAST

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 2
PRO_0000054111Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi407 – 4071N-linked (GlcNAc...) Reviewed prediction
Modified residuei668 – 6681Phosphoserine; by PKG/PRKG2 By 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

ArrayExpressiQ9UL51.
BgeeiQ9UL51.
CleanExiHS_HCN2.
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.1 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

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

3D structure databases

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

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni158 – 20952Involved in subunit assembly By similarity
Add
BLAST

Compositional bias

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

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiCOG0664.
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

MDARGGGGRP GESPGATPAP GPPPPPPPAP PQQQPPPPPP PAPPPGPGPA    50
PPQHPPRAEA LPPEAADEGG PRGRLRSRDS SCGRPGTPGA ASTAKGSPNG 100
ECGRGEPQCS PAGPEGPARG PKVSFSCRGA ASGPAPGPGP AEEAGSEEAG 150
PAGEPRGSQA SFMQRQFGAL LQPGVNKFSL RMFGSQKAVE REQERVKSAG 200
AWIIHPYSDF RFYWDFTMLL FMVGNLIIIP VGITFFKDET TAPWIVFNVV 250
SDTFFLMDLV LNFRTGIVIE DNTEIILDPE KIKKKYLRTW FVVDFVSSIP 300
VDYIFLIVEK GIDSEVYKTA RALRIVRFTK ILSLLRLLRL SRLIRYIHQW 350
EEIFHMTYDL ASAVMRICNL ISMMLLLCHW DGCLQFLVPM LQDFPRNCWV 400
SINGMVNHSW SELYSFALFK AMSHMLCIGY GRQAPESMTD IWLTMLSMIV 450
GATCYAMFIG HATALIQSLD SSRRQYQEKY KQVEQYMSFH KLPADFRQKI 500
HDYYEHRYQG KMFDEDSILG ELNGPLREEI VNFNCRKLVA SMPLFANADP 550
NFVTAMLTKL KFEVFQPGDY IIREGTIGKK MYFIQHGVVS VLTKGNKEMK 600
LSDGSYFGEI CLLTRGRRTA SVRADTYCRL YSLSVDNFNE VLEEYPMMRR 650
AFETVAIDRL DRIGKKNSIL LHKVQHDLNS GVFNNQENAI IQEIVKYDRE 700
MVQQAELGQR VGLFPPPPPP PQVTSAIATL QQAAAMSFCP QVARPLVGPL 750
ALGSPRLVRR PPPGPAPAAA SPGPPPPASP PGAPASPRAP RTSPYGGLPA 800
APLAGPALPA RRLSRASRPL SASQPSLPHG APGPAASTRP ASSSTPRLGP 850
TPAARAAAPS PDRRDSASPG AAGGLDPQDS ARSRLSSNL 889
Length:889
Mass (Da):96,950
Last modified:June 13, 2006 - v3
Checksum:i4B263E0C06C2A47D
GO

Natural variant

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

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti17 – 204TPAP → SPTT in AAC28444. 1 Publication
Sequence conflicti29 – 291A → R in AAC28444. 1 Publication
Sequence conflicti32 – 321Q → K in AAC28444. 1 Publication
Sequence conflicti294 – 2941D → V in AAC39760. 1 Publication
Sequence conflicti713 – 7131L → F in AAC39760. 1 Publication
Sequence conflicti849 – 8491G → R in CAB42602. 1 Publication
Sequence conflicti849 – 8491G → R in CAB42630. 1 Publication

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

EnsembliENST00000251287; ENSP00000251287; ENSG00000099822.
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
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

Ensembli ENST00000251287 ; ENSP00000251287 ; ENSG00000099822 .
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.
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

ArrayExpressi Q9UL51.
Bgeei Q9UL51.
CleanExi HS_HCN2.
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: September 3, 2014
This is version 122 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

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