UniProtKB - Q9UL51 (HCN2_HUMAN)
Protein
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2
Gene
HCN2
Organism
Homo sapiens (Human)
Status
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
Miscellaneous
Inhibited by extracellular cesium ions.
Activity 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 key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Nucleotide bindingi | 608 – 611 | cAMP1 Publication | 4 | |
Nucleotide bindingi | 618 – 619 | cAMP1 Publication | 2 | |
Nucleotide bindingi | 659 – 662 | cAMP1 Publication | 4 |
GO - Molecular functioni
- cAMP binding Source: UniProtKB-KW
- identical protein binding Source: IntAct
- 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
- membrane depolarization during cardiac muscle cell action potential Source: BHF-UCL
- potassium ion import across plasma membrane Source: BHF-UCL
- potassium ion transmembrane transport Source: UniProtKB
- regulation of ion transmembrane transport Source: UniProtKB-KW
- regulation of membrane potential Source: UniProtKB
- sodium ion import across plasma membrane Source: BHF-UCL
- sodium ion transmembrane transport Source: UniProtKB
Keywordsi
Molecular function | Ion channel, Ligand-gated ion channel, Potassium channel, Sodium channel, Voltage-gated channel |
Biological process | Ion transport, Potassium transport, Sodium transport, Transport |
Ligand | cAMP, cAMP-binding, Nucleotide-binding, Potassium, Sodium |
Enzyme and pathway databases
PathwayCommonsi | Q9UL51 |
Reactomei | R-HSA-1296061, HCN channels |
Protein family/group databases
TCDBi | 1.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 2Alternative name(s): Brain cyclic nucleotide-gated channel 2 Short name: BCNG-2 |
Gene namesi | Name:HCN2 Synonyms:BCNG2 |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
EuPathDBi | HostDB:ENSG00000099822.2 |
HGNCi | HGNC:4846, HCN2 |
MIMi | 602781, gene |
neXtProti | NX_Q9UL51 |
Subcellular locationi
Plasma membrane
- Cell membrane 2 Publications; Multi-pass membrane protein 2 Publications
Plasma Membrane
- HCN channel complex Source: BHF-UCL
- integral component of plasma membrane Source: UniProtKB
- plasma membrane Source: UniProtKB
- voltage-gated potassium channel complex Source: ProtInc
Topology
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Topological domaini | 1 – 215 | CytoplasmicSequence analysisAdd BLAST | 215 | |
Transmembranei | 216 – 236 | Helical; Name=Segment S1Sequence analysisAdd BLAST | 21 | |
Topological domaini | 237 – 240 | ExtracellularSequence analysis | 4 | |
Transmembranei | 241 – 261 | Helical; Name=Segment S2Sequence analysisAdd BLAST | 21 | |
Topological domaini | 262 – 288 | CytoplasmicSequence analysisAdd BLAST | 27 | |
Transmembranei | 289 – 309 | Helical; Name=Segment S3Sequence analysisAdd BLAST | 21 | |
Topological domaini | 310 – 317 | ExtracellularSequence analysis | 8 | |
Transmembranei | 318 – 338 | Helical; Voltage-sensor; Name=Segment S4Sequence analysisAdd BLAST | 21 | |
Topological domaini | 339 – 369 | CytoplasmicSequence analysisAdd BLAST | 31 | |
Transmembranei | 370 – 390 | Helical; Name=Segment S5Sequence analysisAdd BLAST | 21 | |
Topological domaini | 391 – 413 | ExtracellularSequence analysisAdd BLAST | 23 | |
Intramembranei | 414 – 435 | Pore-forming; Name=Segment H5Sequence analysisAdd BLAST | 22 | |
Topological domaini | 436 – 440 | ExtracellularSequence analysis | 5 | |
Transmembranei | 441 – 461 | Helical; Name=Segment S6Sequence analysisAdd BLAST | 21 | |
Topological domaini | 462 – 889 | CytoplasmicSequence analysisAdd BLAST | 428 |
Keywords - Cellular componenti
Cell membrane, MembranePathology & Biotechi
Keywords - Diseasei
Disease mutationOrganism-specific databases
DisGeNETi | 610 |
OpenTargetsi | ENSG00000099822 |
PharmGKBi | PA78 |
Miscellaneous databases
Pharosi | Q9UL51, Tclin |
Chemistry databases
ChEMBLi | CHEMBL1795172 |
DrugBanki | DB02527, Cyclic adenosine monophosphate DB02315, Cyclic GMP DB09083, Ivabradine |
DrugCentrali | Q9UL51 |
GuidetoPHARMACOLOGYi | 401 |
Polymorphism and mutation databases
BioMutai | HCN2 |
DMDMi | 108935843 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000054111 | 1 – 889 | Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2Add BLAST | 889 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 146 | PhosphoserineBy similarity | 1 | |
Modified residuei | 161 | PhosphoserineBy similarity | 1 | |
Glycosylationi | 407 | N-linked (GlcNAc...) asparagineSequence analysis | 1 | |
Modified residuei | 668 | Phosphoserine; by PKG/PRKG2By similarity | 1 | |
Modified residuei | 754 | PhosphoserineBy similarity | 1 | |
Modified residuei | 756 | Omega-N-methylarginineBy similarity | 1 | |
Modified residuei | 771 | PhosphoserineBy similarity | 1 | |
Modified residuei | 779 | PhosphoserineBy similarity | 1 | |
Modified residuei | 786 | PhosphoserineBy similarity | 1 | |
Modified residuei | 866 | PhosphoserineBy similarity | 1 | |
Modified residuei | 868 | PhosphoserineBy similarity | 1 |
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, PhosphoproteinProteomic databases
jPOSTi | Q9UL51 |
MassIVEi | Q9UL51 |
MaxQBi | Q9UL51 |
PaxDbi | Q9UL51 |
PeptideAtlasi | Q9UL51 |
PRIDEi | Q9UL51 |
ProteomicsDBi | 84951 |
PTM databases
GlyGeni | Q9UL51, 1 site |
iPTMneti | Q9UL51 |
PhosphoSitePlusi | Q9UL51 |
Expressioni
Tissue specificityi
Highly expressed throughout the brain. Detected at low levels in heart.2 Publications
Gene expression databases
Bgeei | ENSG00000099822, Expressed in C1 segment of cervical spinal cord and 160 other tissues |
Genevisiblei | Q9UL51, HS |
Organism-specific databases
HPAi | ENSG00000099822, Group enriched (brain, heart muscle) |
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 PublicationBinary interactionsi
Hide detailsQ9UL51
With | #Exp. | IntAct |
---|---|---|
itself | 2 | EBI-1751885,EBI-1751885 |
PSEN1 [P49768] | 2 | EBI-1751885,EBI-297277 |
Shank3 - isoform 1 [Q4ACU6-1] from Mus musculus. | 3 | EBI-1751885,EBI-16201983 |
GO - Molecular functioni
- identical protein binding Source: IntAct
Protein-protein interaction databases
BioGRIDi | 107081, 4 interactors |
ComplexPortali | CPX-143, HCN2 channel complex |
DIPi | DIP-52285N |
IntActi | Q9UL51, 8 interactors |
STRINGi | 9606.ENSP00000251287 |
Chemistry databases
BindingDBi | Q9UL51 |
Miscellaneous databases
RNActi | Q9UL51, protein |
Structurei
Secondary structure
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details3D structure databases
BMRBi | Q9UL51 |
SMRi | Q9UL51 |
ModBasei | Search... |
PDBe-KBi | Search... |
Family & Domainsi
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 158 – 209 | Involved in subunit assemblyBy similarityAdd BLAST | 52 |
Compositional bias
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Compositional biasi | 10 – 140 | Pro-richAdd BLAST | 131 | |
Compositional biasi | 715 – 861 | Pro-richAdd BLAST | 147 |
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
Keywords - Domaini
Transmembrane, Transmembrane helixPhylogenomic databases
eggNOGi | KOG0498, Eukaryota |
GeneTreei | ENSGT00940000156523 |
HOGENOMi | CLU_005746_15_1_1 |
InParanoidi | Q9UL51 |
OMAi | MNFCPPM |
OrthoDBi | 281394at2759 |
PhylomeDBi | Q9UL51 |
TreeFami | TF318250 |
Family and domain databases
CDDi | cd00038, CAP_ED, 1 hit |
Gene3Di | 2.60.120.10, 1 hit |
InterProi | View protein in InterPro 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 |
Pfami | View protein in Pfam PF00027, cNMP_binding, 1 hit PF00520, Ion_trans, 1 hit PF08412, Ion_trans_N, 1 hit |
PRINTSi | PR01463, EAGCHANLFMLY |
SMARTi | View protein in SMART SM00100, cNMP, 1 hit |
SUPFAMi | SSF51206, SSF51206, 1 hit |
PROSITEi | View protein in PROSITE PS00888, CNMP_BINDING_1, 1 hit PS50042, CNMP_BINDING_3, 1 hit |
i Sequence
Sequence statusi: Complete.
Q9UL51-1 [UniParc]FASTAAdd to basket
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
Experimental Info
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sequence conflicti | 17 – 20 | TPAP → SPTT in AAC28444 (PubMed:10524219).Curated | 4 | |
Sequence conflicti | 29 | A → R in AAC28444 (PubMed:10524219).Curated | 1 | |
Sequence conflicti | 32 | Q → K in AAC28444 (PubMed:10524219).Curated | 1 | |
Sequence conflicti | 294 | D → V in AAC39760 (PubMed:9630217).Curated | 1 | |
Sequence conflicti | 713 | L → F in AAC39760 (PubMed:9630217).Curated | 1 | |
Sequence conflicti | 849 | G → R in CAB42602 (PubMed:10228147).Curated | 1 | |
Sequence conflicti | 849 | G → R in CAB42630 (PubMed:10228147).Curated | 1 |
Natural variant
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_081530 | 418 | L → V De novo variant found in a patient with childhood apraxia of speech; unknown pathological significance. 1 Publication | 1 | |
Natural variantiVAR_061106 | 527 | R → Q. Corresponds to variant dbSNP:rs55687900Ensembl. | 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 |
CCDSi | CCDS12035.1 |
RefSeqi | NP_001185.3, NM_001194.3 |
Genome annotation databases
Ensembli | ENST00000251287; ENSP00000251287; ENSG00000099822 |
GeneIDi | 610 |
KEGGi | hsa:610 |
UCSCi | uc002lpe.3, human |
Keywords - Coding sequence diversityi
PolymorphismSimilar proteinsi
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 |
CCDSi | CCDS12035.1 |
RefSeqi | NP_001185.3, NM_001194.3 |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
2MPF | NMR | - | A | 521-672 | [»] | |
3U10 | X-ray | 2.30 | A | 470-672 | [»] | |
BMRBi | Q9UL51 | |||||
SMRi | Q9UL51 | |||||
ModBasei | Search... | |||||
PDBe-KBi | Search... |
Protein-protein interaction databases
BioGRIDi | 107081, 4 interactors |
ComplexPortali | CPX-143, HCN2 channel complex |
DIPi | DIP-52285N |
IntActi | Q9UL51, 8 interactors |
STRINGi | 9606.ENSP00000251287 |
Chemistry databases
BindingDBi | Q9UL51 |
ChEMBLi | CHEMBL1795172 |
DrugBanki | DB02527, Cyclic adenosine monophosphate DB02315, Cyclic GMP DB09083, Ivabradine |
DrugCentrali | Q9UL51 |
GuidetoPHARMACOLOGYi | 401 |
Protein family/group databases
TCDBi | 1.A.1.5.11, the voltage-gated ion channel (vic) superfamily |
PTM databases
GlyGeni | Q9UL51, 1 site |
iPTMneti | Q9UL51 |
PhosphoSitePlusi | Q9UL51 |
Polymorphism and mutation databases
BioMutai | HCN2 |
DMDMi | 108935843 |
Proteomic databases
jPOSTi | Q9UL51 |
MassIVEi | Q9UL51 |
MaxQBi | Q9UL51 |
PaxDbi | Q9UL51 |
PeptideAtlasi | Q9UL51 |
PRIDEi | Q9UL51 |
ProteomicsDBi | 84951 |
Protocols and materials databases
Antibodypediai | 22327, 215 antibodies |
DNASUi | 610 |
Genome annotation databases
Ensembli | ENST00000251287; ENSP00000251287; ENSG00000099822 |
GeneIDi | 610 |
KEGGi | hsa:610 |
UCSCi | uc002lpe.3, human |
Organism-specific databases
CTDi | 610 |
DisGeNETi | 610 |
EuPathDBi | HostDB:ENSG00000099822.2 |
GeneCardsi | HCN2 |
HGNCi | HGNC:4846, HCN2 |
HPAi | ENSG00000099822, Group enriched (brain, heart muscle) |
MIMi | 602781, gene |
neXtProti | NX_Q9UL51 |
OpenTargetsi | ENSG00000099822 |
PharmGKBi | PA78 |
GenAtlasi | Search... |
Phylogenomic databases
eggNOGi | KOG0498, Eukaryota |
GeneTreei | ENSGT00940000156523 |
HOGENOMi | CLU_005746_15_1_1 |
InParanoidi | Q9UL51 |
OMAi | MNFCPPM |
OrthoDBi | 281394at2759 |
PhylomeDBi | Q9UL51 |
TreeFami | TF318250 |
Enzyme and pathway databases
PathwayCommonsi | Q9UL51 |
Reactomei | R-HSA-1296061, HCN channels |
Miscellaneous databases
BioGRID-ORCSi | 610, 10 hits in 819 CRISPR screens |
ChiTaRSi | HCN2, human |
GeneWikii | HCN2 |
GenomeRNAii | 610 |
Pharosi | Q9UL51, Tclin |
PROi | PR:Q9UL51 |
RNActi | Q9UL51, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSG00000099822, Expressed in C1 segment of cervical spinal cord and 160 other tissues |
Genevisiblei | Q9UL51, HS |
Family and domain databases
CDDi | cd00038, CAP_ED, 1 hit |
Gene3Di | 2.60.120.10, 1 hit |
InterProi | View protein in InterPro 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 |
Pfami | View protein in Pfam PF00027, cNMP_binding, 1 hit PF00520, Ion_trans, 1 hit PF08412, Ion_trans_N, 1 hit |
PRINTSi | PR01463, EAGCHANLFMLY |
SMARTi | View protein in SMART SM00100, cNMP, 1 hit |
SUPFAMi | SSF51206, SSF51206, 1 hit |
PROSITEi | View protein in PROSITE PS00888, CNMP_BINDING_1, 1 hit PS50042, CNMP_BINDING_3, 1 hit |
ProtoNeti | Search... |
MobiDBi | Search... |
Entry informationi
Entry namei | HCN2_HUMAN | |
Accessioni | Q9UL51Primary (citable) accession number: Q9UL51 Secondary accession number(s): O60742 Q9UBS2 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | February 28, 2003 |
Last sequence update: | June 13, 2006 | |
Last modified: | December 2, 2020 | |
This is version 173 of the entry and version 3 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program | |
Disclaimer | Any 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
Keywords - Technical termi
3D-structure, Reference proteomeDocuments
- Human polymorphisms and disease mutations
Index of human polymorphisms and disease mutations - MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot - PDB cross-references
Index of Protein Data Bank (PDB) cross-references - SIMILARITY comments
Index of protein domains and families - Human chromosome 19
Human chromosome 19: entries, gene names and cross-references to MIM - Human entries with polymorphisms or disease mutations
List of human entries with polymorphisms or disease mutations