Q9UL51 (HCN2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	HCN2
Synonyms:	BCNG2

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	889 AA.
Sequence status	Complete.
Protein existence	Evidence 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. Activated by cAMP. Modulated by intracellular chloride ions and pH; acidic pH shifts the activation to more negative voltages By similarity.
Subunit structure	The potassium channel is composed of a homo- or heterotetrameric complex of pore-forming subunits. Heteromultimer with HCN1. Forms an obligate 4:4 complex with accessory subunit PEX5L. Interacts with KCNE2 By similarity.
Subcellular location	Membrane; Multi-pass membrane protein.
Tissue specificity	Highly expressed throughout the brain. Detected at low levels in heart. 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 process	Ion transport Potassium transport Sodium transport Transport
Cellular component	Membrane
Coding sequence diversity	Polymorphism
Domain	Transmembrane Transmembrane helix
Ligand	Nucleotide-binding Potassium Sodium cAMP cAMP-binding
Molecular function	Ion channel Ligand-gated ion channel Potassium channel Sodium channel Voltage-gated channel
PTM	Glycoprotein Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	muscle contraction Traceable author statement Ref.2. Source: ProtInc regulation of membrane potential Inferred from electronic annotation. Source: Compara sodium ion transmembrane transport Inferred from electronic annotation. Source: GOC synaptic transmission Traceable author statement. Source: Reactome
Cellular_component	voltage-gated potassium channel complex Traceable author statement Ref.4. Source: ProtInc
Molecular_function	cAMP binding Inferred from electronic annotation. Source: UniProtKB-KW cation channel activity Traceable author statement Ref.2. Source: ProtInc sodium channel activity Inferred from electronic annotation. Source: UniProtKB-KW voltage-gated potassium channel activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 889

889

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

PRO_0000054111

Regions

Topological domain

1 – 215

215

Cytoplasmic Potential

Transmembrane

216 – 236

21

Helical; Name=Segment S1; Potential

Topological domain

237 – 240

4

Extracellular Potential

Transmembrane

241 – 261

21

Helical; Name=Segment S2; Potential

Topological domain

262 – 288

27

Cytoplasmic Potential

Transmembrane

289 – 309

21

Helical; Name=Segment S3; Potential

Topological domain

310 – 317

8

Extracellular Potential

Transmembrane

318 – 338

21

Helical; Voltage-sensor; Name=Segment S4; Potential

Topological domain

339 – 369

31

Cytoplasmic Potential

Transmembrane

370 – 390

21

Helical; Name=Segment S5; Potential

Topological domain

391 – 413

23

Extracellular Potential

Intramembrane

414 – 435

22

Pore-forming; Name=Segment H5; Potential

Topological domain

436 – 440

5

Extracellular Potential

Transmembrane

441 – 461

21

Helical; Name=Segment S6; Potential

Topological domain

462 – 889

428

Cytoplasmic Potential

Nucleotide binding

544 – 661

118

cAMP

Region

158 – 209

52

Involved in subunit assembly By similarity

Compositional bias

10 – 140

131

Pro-rich

Compositional bias

715 – 861

147

Pro-rich

Amino acid modifications

Modified residue

146

1

Phosphoserine By similarity

Modified residue

668

1

Phosphoserine; by PKG/PRKG2 By similarity

Modified residue

779

1

Phosphoserine By similarity

Glycosylation

407

1

N-linked (GlcNAc...) Potential

Natural variations

Natural variant

527

1

R → Q.
Corresponds to variant rs55687900 [ dbSNP | Ensembl ].

VAR_061106

Experimental info

Sequence conflict

17 – 20

4

TPAP → SPTT in AAC28444. Ref.1

Sequence conflict

29

1

A → R in AAC28444. Ref.1

Sequence conflict

32

1

Q → K in AAC28444. Ref.1

Sequence conflict

294

1

D → V in AAC39760. Ref.4

Sequence conflict

713

1

L → F in AAC39760. Ref.4

Sequence conflict

849

1

G → R in CAB42602. Ref.2

Sequence conflict

849

1

G → R in CAB42630. Ref.2

Secondary structure

1

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889

Helix Strand Turn

Details...

Helix

471 – 489

19

Helix

494 – 508

15

Helix

515 – 520

6

Helix

524 – 534

11

Helix

536 – 540

5

Turn

543 – 547

5

Helix

550 – 557

8

Beta strand

561 – 565

5

Beta strand

570 – 572

3

Beta strand

580 – 586

7

Beta strand

589 – 592

4

Beta strand

598 – 601

4

Beta strand

606 – 608

3

Helix

610 – 614

5

Beta strand

619 – 626

8

Beta strand

628 – 634

7

Helix

635 – 644

10

Helix

646 – 661

16

Turn

662 – 664

3

Helix

668 – 670

3

Sequences

	Sequence		Length	Mass (Da)
	Q9UL51 [UniParc]. Last modified June 13, 2006. Version 3. Checksum: 4B263E0C06C2A47D	FASTA	889	96,950
	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

References

	« Hide 'large scale' referencesShow '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].
[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], CHARACTERIZATION. 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]	"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.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

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.

IPI

IPI00218946.

RefSeq

NP_001185.3. NM_001194.3.

UniGene

Hs.124161.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3U10	X-ray	2.30	A	470-672	[»]

ProteinModelPortal

Q9UL51.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9UL51. 4 interactions.

MINT

MINT-2821972.

STRING

9606.ENSP00000251287.

PTM databases

PhosphoSite

Q9UL51.

Polymorphism databases

DMDM

108935843.

Proteomic databases

PaxDb

Q9UL51.

PRIDE

Q9UL51.

Protocols and materials databases

DNASU

610.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000251287; ENSP00000251287; ENSG00000099822.

GeneID

610.

KEGG

hsa:610.

UCSC

uc002lpe.3. human.

Organism-specific databases

CTD

610.

GeneCards

GC19P000589.

HGNC

HGNC:4846. HCN2.

MIM

602781. gene.

neXtProt

NX_Q9UL51.

PharmGKB

PA78.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0664.

HOGENOM

HOG000230717.

HOVERGEN

HBG039489.

InParanoid

Q9UL51.

KO

K04955.

OMA

ECGRGEP.

OrthoDB

EOG46Q6S8.

PhylomeDB

Q9UL51.

Enzyme and pathway databases

Reactome

REACT_13685. Neuronal System.

Gene expression databases

ArrayExpress

Q9UL51.

Bgee

Q9UL51.

CleanEx

HS_HCN2.

Genevestigator

Q9UL51.

GermOnline

ENSG00000099822. Homo sapiens.

Family and domain databases

Gene3D

2.60.120.10. 1 hit.

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.
[Graphical view]

Pfam

PF00027. cNMP_binding. 1 hit.
PF00520. Ion_trans. 1 hit.
PF08412. Ion_trans_N. 1 hit.
[Graphical view]

PRINTS

PR01463. EAGCHANLFMLY.

SMART

SM00100. cNMP. 1 hit.
[Graphical view]

SUPFAM

SSF51206. cNMP_binding. 1 hit.

PROSITE

PS00888. CNMP_BINDING_1. 1 hit.
PS00889. CNMP_BINDING_2. False negative.
PS50042. CNMP_BINDING_3. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChEMBL

CHEMBL1795172.

GenomeRNAi

610.

NextBio

2477.

SOURCE

Search...

Entry information

Entry name

HCN2_HUMAN

Accession

Primary (citable) accession number: Q9UL51
Secondary accession number(s): O60742 , O60743, O75267, Q9UBS2

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 28, 2003
Last sequence update:	June 13, 2006
Last modified:	May 1, 2013
This is version 109 of the entry and version 3 of the sequence. [Complete history]

Entry status

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.