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Protein

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

Gene

HCN2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: 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 similarity2 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)DescriptionActionsGraphical viewLength
Nucleotide bindingi608 – 611cAMP1 Publication4
Nucleotide bindingi618 – 619cAMP1 Publication2
Nucleotide bindingi659 – 662cAMP1 Publication4

GO - Molecular functioni

  • cAMP binding Source: UniProtKB-KW
  • intracellular cAMP activated cation channel activity Source: UniProtKB
  • voltage-gated potassium channel activity Source: UniProtKB
  • voltage-gated sodium channel activity Source: UniProtKB

GO - Biological processi

  • cell-cell signaling Source: ProtInc
  • cellular response to cAMP Source: UniProtKB
  • cellular response to cGMP Source: UniProtKB
  • potassium ion transmembrane transport Source: UniProtKB
  • regulation of membrane potential Source: UniProtKB
  • sodium ion transmembrane transport Source: UniProtKB
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

ReactomeiR-HSA-1296061. 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
Proteomesi
  • UP000005640 Componenti: Chromosome 19

Organism-specific databases

HGNCiHGNC:4846. HCN2.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 215CytoplasmicSequence analysisAdd BLAST215
Transmembranei216 – 236Helical; Name=Segment S1Sequence analysisAdd BLAST21
Topological domaini237 – 240ExtracellularSequence analysis4
Transmembranei241 – 261Helical; Name=Segment S2Sequence analysisAdd BLAST21
Topological domaini262 – 288CytoplasmicSequence analysisAdd BLAST27
Transmembranei289 – 309Helical; Name=Segment S3Sequence analysisAdd BLAST21
Topological domaini310 – 317ExtracellularSequence analysis8
Transmembranei318 – 338Helical; Voltage-sensor; Name=Segment S4Sequence analysisAdd BLAST21
Topological domaini339 – 369CytoplasmicSequence analysisAdd BLAST31
Transmembranei370 – 390Helical; Name=Segment S5Sequence analysisAdd BLAST21
Topological domaini391 – 413ExtracellularSequence analysisAdd BLAST23
Intramembranei414 – 435Pore-forming; Name=Segment H5Sequence analysisAdd BLAST22
Topological domaini436 – 440ExtracellularSequence analysis5
Transmembranei441 – 461Helical; Name=Segment S6Sequence analysisAdd BLAST21
Topological domaini462 – 889CytoplasmicSequence analysisAdd BLAST428

GO - Cellular componenti

  • integral component of plasma membrane Source: UniProtKB
  • plasma membrane Source: UniProtKB
  • voltage-gated potassium channel complex Source: ProtInc
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Organism-specific databases

DisGeNETi610.
OpenTargetsiENSG00000099822.
PharmGKBiPA78.

Chemistry databases

ChEMBLiCHEMBL1795172.
GuidetoPHARMACOLOGYi401.

Polymorphism and mutation databases

BioMutaiHCN2.
DMDMi108935843.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000541111 – 889Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2Add BLAST889

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei146PhosphoserineBy similarity1
Modified residuei161PhosphoserineBy similarity1
Glycosylationi407N-linked (GlcNAc...)Sequence analysis1
Modified residuei668Phosphoserine; by PKG/PRKG2By similarity1
Modified residuei754PhosphoserineBy similarity1
Modified residuei756Omega-N-methylarginineBy similarity1
Modified residuei771PhosphoserineBy similarity1
Modified residuei779PhosphoserineBy similarity1
Modified residuei786PhosphoserineBy similarity1
Modified residuei866PhosphoserineBy similarity1
Modified residuei868PhosphoserineBy similarity1

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, Methylation, Phosphoprotein

Proteomic databases

MaxQBiQ9UL51.
PaxDbiQ9UL51.
PeptideAtlasiQ9UL51.
PRIDEiQ9UL51.

PTM databases

iPTMnetiQ9UL51.
PhosphoSitePlusiQ9UL51.

Expressioni

Tissue specificityi

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

Gene expression databases

BgeeiENSG00000099822.
CleanExiHS_HCN2.
GenevisibleiQ9UL51. HS.

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 interactors.
DIPiDIP-52285N.
IntActiQ9UL51. 5 interactors.
STRINGi9606.ENSP00000251287.

Chemistry databases

BindingDBiQ9UL51.

Structurei

Secondary structure

1889
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi471 – 489Combined sources19
Helixi494 – 508Combined sources15
Helixi515 – 520Combined sources6
Helixi524 – 534Combined sources11
Helixi536 – 540Combined sources5
Turni543 – 547Combined sources5
Helixi550 – 557Combined sources8
Beta strandi561 – 565Combined sources5
Beta strandi570 – 572Combined sources3
Beta strandi576 – 578Combined sources3
Beta strandi580 – 586Combined sources7
Beta strandi589 – 592Combined sources4
Beta strandi598 – 601Combined sources4
Beta strandi606 – 608Combined sources3
Helixi610 – 614Combined sources5
Beta strandi619 – 626Combined sources8
Beta strandi628 – 634Combined sources7
Helixi635 – 644Combined sources10
Helixi646 – 661Combined sources16
Turni662 – 664Combined sources3
Helixi668 – 670Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2MPFNMR-A521-672[»]
3U10X-ray2.30A470-672[»]
ProteinModelPortaliQ9UL51.
SMRiQ9UL51.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni158 – 209Involved in subunit assemblyBy similarityAdd BLAST52

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi10 – 140Pro-richAdd BLAST131
Compositional biasi715 – 861Pro-richAdd BLAST147

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

eggNOGiKOG0498. Eukaryota.
ENOG410XPSE. LUCA.
GeneTreeiENSGT00760000118772.
HOGENOMiHOG000230717.
HOVERGENiHBG039489.
InParanoidiQ9UL51.
KOiK04955.
OMAiMRICNIS.
OrthoDBiEOG091G0JQU.
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)DescriptionActionsGraphical viewLength
Sequence conflicti17 – 20TPAP → SPTT in AAC28444 (PubMed:10524219).Curated4
Sequence conflicti29A → R in AAC28444 (PubMed:10524219).Curated1
Sequence conflicti32Q → K in AAC28444 (PubMed:10524219).Curated1
Sequence conflicti294D → V in AAC39760 (PubMed:9630217).Curated1
Sequence conflicti713L → F in AAC39760 (PubMed:9630217).Curated1
Sequence conflicti849G → R in CAB42602 (PubMed:10228147).Curated1
Sequence conflicti849G → R in CAB42630 (PubMed:10228147).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_061106527R → Q.Corresponds to variant rs55687900dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
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.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
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.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2MPFNMR-A521-672[»]
3U10X-ray2.30A470-672[»]
ProteinModelPortaliQ9UL51.
SMRiQ9UL51.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi107081. 4 interactors.
DIPiDIP-52285N.
IntActiQ9UL51. 5 interactors.
STRINGi9606.ENSP00000251287.

Chemistry databases

BindingDBiQ9UL51.
ChEMBLiCHEMBL1795172.
GuidetoPHARMACOLOGYi401.

Protein family/group databases

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

PTM databases

iPTMnetiQ9UL51.
PhosphoSitePlusiQ9UL51.

Polymorphism and mutation databases

BioMutaiHCN2.
DMDMi108935843.

Proteomic databases

MaxQBiQ9UL51.
PaxDbiQ9UL51.
PeptideAtlasiQ9UL51.
PRIDEiQ9UL51.

Protocols and materials databases

DNASUi610.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000251287; ENSP00000251287; ENSG00000099822.
GeneIDi610.
KEGGihsa:610.
UCSCiuc002lpe.3. human.

Organism-specific databases

CTDi610.
DisGeNETi610.
GeneCardsiHCN2.
HGNCiHGNC:4846. HCN2.
MIMi602781. gene.
neXtProtiNX_Q9UL51.
OpenTargetsiENSG00000099822.
PharmGKBiPA78.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0498. Eukaryota.
ENOG410XPSE. LUCA.
GeneTreeiENSGT00760000118772.
HOGENOMiHOG000230717.
HOVERGENiHBG039489.
InParanoidiQ9UL51.
KOiK04955.
OMAiMRICNIS.
OrthoDBiEOG091G0JQU.
PhylomeDBiQ9UL51.
TreeFamiTF318250.

Enzyme and pathway databases

ReactomeiR-HSA-1296061. HCN channels.

Miscellaneous databases

GeneWikiiHCN2.
GenomeRNAii610.
PROiQ9UL51.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000099822.
CleanExiHS_HCN2.
GenevisibleiQ9UL51. HS.

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]
ProtoNetiSearch...

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: November 2, 2016
This is version 142 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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.