Q9Y3Q4 (HCN4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4

Gene names

Name:

HCN4

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	1203 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Hyperpolarization-activated ion channel with very slow activation and inactivation exhibiting weak selectivity for potassium over sodium ions. May contribute to the native pacemaker currents in heart (If) and in neurons (Ih). Activated by cAMP. May mediate responses to sour stimuli. Ref.1 Ref.2
Subunit structure	The potassium channel is probably composed of a homo- or heterotetrameric complex of pore-forming subunits.
Subcellular location	Membrane; Multi-pass membrane protein.
Tissue specificity	Highly expressed in thalamus, testis and in heart, both in ventricle and atrium. Detected at much lower levels in amygdala, substantia nigra, cerebellum and hippocampus.
Domain	The segment S4 is probably the voltage-sensor and is characterized by a series of positively charged amino acids at every third position.
Involvement in disease	Sick sinus syndrome 2 (SSS2) [MIM:163800]: The term 'sick sinus syndrome' encompasses a variety of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope, dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors. SSS2 onset is in utero or at birth. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.5 Ref.6 Brugada syndrome 8 (BRGDA8) [MIM:613123]: A tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.3
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
Disease	Brugada syndrome Disease mutation
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	blood circulation Non-traceable author statement Ref.1. Source: ProtInc in utero embryonic development Inferred from electronic annotation. Source: Compara muscle contraction Traceable author statement Ref.1. Source: ProtInc regulation of heart contraction 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	integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW plasma membrane Traceable author statement. Source: Reactome terminal bouton Inferred from electronic annotation. Source: Compara
Molecular_function	cAMP binding Inferred from electronic annotation. Source: UniProtKB-KW cation channel activity Traceable author statement Ref.1. Source: ProtInc intracellular cAMP activated cation channel activity Inferred from electronic annotation. Source: Compara 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 – 1203

1203

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4

PRO_0000054117

Regions

Topological domain

1 – 266

266

Cytoplasmic Potential

Transmembrane

267 – 287

21

Helical; Name=Segment S1; Potential

Topological domain

288 – 293

6

Extracellular Potential

Transmembrane

294 – 314

21

Helical; Name=Segment S2; Potential

Topological domain

315 – 340

26

Cytoplasmic Potential

Transmembrane

341 – 361

21

Helical; Name=Segment S3; Potential

Topological domain

362 – 368

7

Extracellular Potential

Transmembrane

369 – 389

21

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

Topological domain

390 – 420

31

Cytoplasmic Potential

Transmembrane

421 – 441

21

Helical; Name=Segment S5; Potential

Topological domain

442 – 464

23

Extracellular Potential

Intramembrane

465 – 486

22

Pore-forming; Name=Segment H5; Potential

Topological domain

487 – 496

10

Extracellular Potential

Transmembrane

497 – 517

21

Helical; Name=Segment S6; Potential

Topological domain

518 – 1203

686

Cytoplasmic Potential

Nucleotide binding

595 – 710

116

cAMP

Region

209 – 260

52

Involved in subunit assembly By similarity

Compositional bias

924 – 1076

153

Pro-rich

Amino acid modifications

Modified residue

935

1

Phosphoserine By similarity

Glycosylation

458

1

N-linked (GlcNAc...) Potential

Natural variations

Natural variant

485

1

A → V in SSS2; results in a significant reduction of current density compared to wild-type. Ref.6

VAR_066614

Natural variant

553

1

D → N in a patient with cardiac arrhythmia. Ref.4

VAR_026534

Natural variant

672

1

S → R in SSS2; does not affect cAMP-induced channel activation; causes shifting of the current activation range to hyperpolarized voltages. Ref.5

VAR_026535

Experimental info

Sequence conflict

110

1

S → T in CAB52754. Ref.2

Secondary structure

1

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1203

Helix Strand Turn

Details...

Helix

522 – 540

19

Helix

545 – 559

15

Helix

566 – 571

6

Helix

575 – 585

11

Helix

587 – 591

5

Helix

594 – 597

4

Helix

601 – 608

8

Beta strand

612 – 616

5

Beta strand

621 – 623

3

Beta strand

631 – 637

7

Beta strand

640 – 643

4

Beta strand

645 – 647

3

Beta strand

650 – 652

3

Helix

661 – 665

5

Beta strand

670 – 677

8

Beta strand

679 – 685

7

Helix

686 – 695

10

Helix

697 – 699

3

Helix

700 – 712

13

Sequences

	Sequence		Length	Mass (Da)
	Q9Y3Q4 [UniParc]. Last modified November 1, 1999. Version 1. Checksum: 7EFDD2D69CF1F9D9	FASTA	1,203	129,042
	10 20 30 40 50 60 MDKLPPSMRK RLYSLPQQVG AKAWIMDEEE DAEEEGAGGR QDPSRRSIRL RPLPSPSPSA 70 80 90 100 110 120 AAGGTESRSS ALGAADSEGP ARGAGKSSTN GDCRRFRGSL ASLGSRGGGS GGTGSGSSHG 130 140 150 160 170 180 HLHDSAEERR LIAEGDASPG EDRTPPGLAA EPERPGASAQ PAASPPPPQQ PPQPASASCE 190 200 210 220 230 240 QPSVDTAIKV EGGAAAGDQI LPEAEVRLGQ AGFMQRQFGA MLQPGVNKFS LRMFGSQKAV 250 260 270 280 290 300 EREQERVKSA GFWIIHPYSD FRFYWDLTML LLMVGNLIII PVGITFFKDE NTTPWIVFNV 310 320 330 340 350 360 VSDTFFLIDL VLNFRTGIVV EDNTEIILDP QRIKMKYLKS WFMVDFISSI PVDYIFLIVE 370 380 390 400 410 420 TRIDSEVYKT ARALRIVRFT KILSLLRLLR LSRLIRYIHQ WEEIFHMTYD LASAVVRIVN 430 440 450 460 470 480 LIGMMLLLCH WDGCLQFLVP MLQDFPDDCW VSINNMVNNS WGKQYSYALF KAMSHMLCIG 490 500 510 520 530 540 YGRQAPVGMS DVWLTMLSMI VGATCYAMFI GHATALIQSL DSSRRQYQEK YKQVEQYMSF 550 560 570 580 590 600 HKLPPDTRQR IHDYYEHRYQ GKMFDEESIL GELSEPLREE IINFNCRKLV ASMPLFANAD 610 620 630 640 650 660 PNFVTSMLTK LRFEVFQPGD YIIREGTIGK KMYFIQHGVV SVLTKGNKET KLADGSYFGE 670 680 690 700 710 720 ICLLTRGRRT ASVRADTYCR LYSLSVDNFN EVLEEYPMMR RAFETVALDR LDRIGKKNSI 730 740 750 760 770 780 LLHKVQHDLN SGVFNYQENE IIQQIVQHDR EMAHCAHRVQ AAASATPTPT PVIWTPLIQA 790 800 810 820 830 840 PLQAAAATTS VAIALTHHPR LPAAIFRPPP GSGLGNLGAG QTPRHLKRLQ SLIPSALGSA 850 860 870 880 890 900 SPASSPSQVD TPSSSSFHIQ QLAGFSAPAG LSPLLPSSSS SPPPGACGSP SAPTPSAGVA 910 920 930 940 950 960 ATTIAGFGHF HKALGGSLSS SDSPLLTPLQ PGARSPQAAQ PSPAPPGARG GLGLPEHFLP 970 980 990 1000 1010 1020 PPPSSRSPSS SPGQLGQPPG ELSLGLATGP LSTPETPPRQ PEPPSLVAGA SGGASPVGFT 1030 1040 1050 1060 1070 1080 PRGGLSPPGH SPGPPRTFPS APPRASGSHG SLLLPPASSP PPPQVPQRRG TPPLTPGRLT 1090 1100 1110 1120 1130 1140 QDLKLISASQ PALPQDGAQT LRRASPHSSG ESMAAFPLFP RAGGGSGGSG SSGGLGPPGR 1150 1160 1170 1180 1190 1200 PYGAIPGQHV TLPRKTSSGS LPPPLSLFGA RATSSGGPPL TAGPQREPGA RPEPVRSKLP SNL

References

[1]	"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 [MRNA], FUNCTION. Tissue: Heart.
[2]	"Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis." Seifert R., Scholten A., Gauss R., Mincheva A., Lichter P., Kaupp U.B. Proc. Natl. Acad. Sci. U.S.A. 96:9391-9396(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION. Tissue: Thalamus.
[3]	"Role of HCN4 channel in preventing ventricular arrhythmia." Ueda K., Hirano Y., Higashiuesato Y., Aizawa Y., Hayashi T., Inagaki N., Tana T., Ohya Y., Takishita S., Muratani H., Hiraoka M., Kimura A. J. Hum. Genet. 54:115-121(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN BRGDA8.
[4]	"Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia." Ueda K., Nakamura K., Hayashi T., Inagaki N., Takahashi M., Arimura T., Morita H., Higashiuesato Y., Hirano Y., Yasunami M., Takishita S., Yamashina A., Ohe T., Sunamori M., Hiraoka M., Kimura A. J. Biol. Chem. 279:27194-27198(2004) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT CARDIAC ARRHYTHMIA ASN-553.
[5]	"Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel." Milanesi R., Baruscotti M., Gnecchi-Ruscone T., DiFrancesco D. N. Engl. J. Med. 354:151-157(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT SSS2 ARG-672, CHARACTERIZATION OF VARIANT SSS2 ARG-672.
[6]	"A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in Moroccan Jews." Laish-Farkash A., Glikson M., Brass D., Marek-Yagel D., Pras E., Dascal N., Antzelevitch C., Nof E., Reznik H., Eldar M., Luria D. J. Cardiovasc. Electrophysiol. 21:1365-1372(2010) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT SSS2 VAL-485, CHARACTERIZATION OF VARIANT SSS2 VAL-485.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AJ132429 mRNA. Translation: CAB42604.1.
AJ238850 mRNA. Translation: CAB52754.1.

IPI

IPI00023164.

RefSeq

NP_005468.1. NM_005477.2.

UniGene

Hs.86941.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3OTF	X-ray	2.40	A	521-739	[»]
3U11	X-ray	2.50	A/B	521-723	[»]
4HBN	X-ray	2.60	A	521-724	[»]

ProteinModelPortal

Q9Y3Q4.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9Y3Q4. 2 interactions.

STRING

9606.ENSP00000261917.

PTM databases

PhosphoSite

Q9Y3Q4.

Polymorphism databases

DMDM

38605641.

Proteomic databases

PaxDb

Q9Y3Q4.

PRIDE

Q9Y3Q4.

Protocols and materials databases

DNASU

10021.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000261917; ENSP00000261917; ENSG00000138622.

GeneID

10021.

KEGG

hsa:10021.

UCSC

uc002avp.3. human.

Organism-specific databases

CTD

10021.

GeneCards

GC15M073612.

HGNC

HGNC:16882. HCN4.

MIM

163800. phenotype.
605206. gene.
613123. phenotype.

neXtProt

NX_Q9Y3Q4.

Orphanet

130. Brugada syndrome.
166282. Sick sinus syndrome.

PharmGKB

PA394.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0664.

HOGENOM

HOG000230717.

HOVERGEN

HBG039490.

InParanoid

Q9Y3Q4.

KO

K04957.

OMA

LEHFLPP.

OrthoDB

EOG46Q6S8.

PhylomeDB

Q9Y3Q4.

Enzyme and pathway databases

Reactome

REACT_13685. Neuronal System.

Gene expression databases

Bgee

Q9Y3Q4.

CleanEx

HS_HCN4.

Genevestigator

Q9Y3Q4.

GermOnline

ENSG00000138622. 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

BindingDB

Q9Y3Q4.

ChEMBL

CHEMBL1250417.

EvolutionaryTrace

Q9Y3Q4.

GenomeRNAi

10021.

NextBio

37865.

SOURCE

Search...

Entry information

Entry name

HCN4_HUMAN

Accession

Primary (citable) accession number: Q9Y3Q4
Secondary accession number(s): Q9UMQ7

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 28, 2003
Last sequence update:	November 1, 1999
Last modified:	May 29, 2013
This is version 112 of the entry and version 1 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.