Protein Annotations for Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4, HCN4

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Name	Gene Symbol	Rec Full Name	Protein Information	Quick Quote	Price, Turnaround
HCN4_HUMAN, Homo sapiens (human)	HCN4	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4	Functions		Quote
HCN4_HUMAN, Homo sapiens (human)	HCN4		Protein Domains		Quote

Protein Names

Recommended name:	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4;
Alternative name(s):

Protein IDs
(Accession numbers)

UniProtKB	Q9Y3Q4
NCBI RefSeq	NP_005468.1, NM_005477.2.

Organism

Latin Name/ (Common Name)	Homo sapiens (Human).
Taxonomic Identifier (NCBI)	9606

Gene Names

HCN4 [GenPool]

GeneID

10021

Genome
Annotation (Ensembl)

ENST00000261917, ENSP00000261917; ENSG00000138622

Protein Sequence

SEQUENCE   1203 AA;  129042 MW;  7EFDD2D69CF1F9D9 CRC64;
MDKLPPSMRK RLYSLPQQVG AKAWIMDEEE DAEEEGAGGR QDPSRRSIRL RPLPSPSPSA
AAGGTESRSS ALGAADSEGP ARGAGKSSTN GDCRRFRGSL ASLGSRGGGS GGTGSGSSHG
HLHDSAEERR LIAEGDASPG EDRTPPGLAA EPERPGASAQ PAASPPPPQQ PPQPASASCE
QPSVDTAIKV EGGAAAGDQI LPEAEVRLGQ AGFMQRQFGA MLQPGVNKFS LRMFGSQKAV
EREQERVKSA GFWIIHPYSD FRFYWDLTML LLMVGNLIII PVGITFFKDE NTTPWIVFNV
VSDTFFLIDL VLNFRTGIVV EDNTEIILDP QRIKMKYLKS WFMVDFISSI PVDYIFLIVE
TRIDSEVYKT ARALRIVRFT KILSLLRLLR LSRLIRYIHQ WEEIFHMTYD LASAVVRIVN
LIGMMLLLCH WDGCLQFLVP MLQDFPDDCW VSINNMVNNS WGKQYSYALF KAMSHMLCIG
YGRQAPVGMS DVWLTMLSMI VGATCYAMFI GHATALIQSL DSSRRQYQEK YKQVEQYMSF
HKLPPDTRQR IHDYYEHRYQ GKMFDEESIL GELSEPLREE IINFNCRKLV ASMPLFANAD
PNFVTSMLTK LRFEVFQPGD YIIREGTIGK KMYFIQHGVV SVLTKGNKET KLADGSYFGE
ICLLTRGRRT ASVRADTYCR LYSLSVDNFN EVLEEYPMMR RAFETVALDR LDRIGKKNSI
LLHKVQHDLN SGVFNYQENE IIQQIVQHDR EMAHCAHRVQ AAASATPTPT PVIWTPLIQA
PLQAAAATTS VAIALTHHPR LPAAIFRPPP GSGLGNLGAG QTPRHLKRLQ SLIPSALGSA
SPASSPSQVD TPSSSSFHIQ QLAGFSAPAG LSPLLPSSSS SPPPGACGSP SAPTPSAGVA
ATTIAGFGHF HKALGGSLSS SDSPLLTPLQ PGARSPQAAQ PSPAPPGARG GLGLPEHFLP
PPPSSRSPSS SPGQLGQPPG ELSLGLATGP LSTPETPPRQ PEPPSLVAGA SGGASPVGFT
PRGGLSPPGH SPGPPRTFPS APPRASGSHG SLLLPPASSP PPPQVPQRRG TPPLTPGRLT
QDLKLISASQ PALPQDGAQT LRRASPHSSG ESMAAFPLFP RAGGGSGGSG SSGGLGPPGR
PYGAIPGQHV TLPRKTSSGS LPPPLSLFGA RATSSGGPPL TAGPQREPGA RPEPVRSKLP
SNL

General annotation

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.
Cofactor
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.
Induction
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
Involvement in disease	Defects in HCN4 are a cause of sick sinus syndrome type 2 (SSS2) [MIM:163800]; also known as atrial fibrillation with bradyarrhythmia or familial sinus bradycardia. 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, in which case it is considered to be a congenital disorder. Defects in HCN4 are the cause of Brugada syndrome type 8 (BRS8) [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 (called ventricular fibrillation), the individual will faint and may die in a few minutes if the heart is not reset.

References

"Two pacemaker channels from human heart with profoundly differentactivation kinetics.";,Ludwig A., Zong X., Stieber J., Hullin R., Hofmann F., Biel M.;,EMBO J. 18:2323-2329(1999)., PubMeb:10228147 DOI:10.1093/emboj/18.9.2323
"Molecular characterization of a slowly gating humanhyperpolarization-activated channel predominantly expressed inthalamus, 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)., PubMeb:10430953 DOI:10.1073/pnas.96.16.9391
"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).,PubMeb:19165230 DOI:10.1038/jhg.2008.16
"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).,PubMeb:15123648 DOI:10.1074/jbc.M311953200
"Familial sinus bradycardia associated with a mutation in the cardiacpacemaker channel.";,Milanesi R., Baruscotti M., Gnecchi-Ruscone T., DiFrancesco D.;,N. Engl. J. Med. 354:151-157(2006).,PubMeb:16407510 DOI:10.1056/NEJMoa052475

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Protein Domain Databases

InterPro	IPR018490, cNMP-bd-like. IPR018488, cNMP-bd_CS. IPR000595, cNMP-bd_dom. IPR005821, Ion_trans. IPR013621, Ion_trans_N. IPR003938, K_chnl_volt-dep_EAG/ELK/ERG. IPR014710, RmlC-like_jellyroll.
Gene3D	G3DSA:2.60.120.10, RmlC-like_jellyroll; 1.
PANTHER
Pfam	PF00027, cNMP_binding; 1. PF00520, Ion_trans; 1. PF08412, Ion_trans_N; 1.
PRINTS	PR01463, EAGCHANLFMLY.
SUPFAM	SSF51206, cNMP_binding; 1.
PROSITE	PS00888, CNMP_BINDING_1; 1. PS00889, CNMP_BINDING_2; FALSE_NEG. PS50042, CNMP_BINDING_3; 1.

3D Structure
Database (PDB)

Entry	Method	Resolution (A)	Chain	Positions	PDBsum
3OTF	X-ray	2.40 A	A	521-739	[>>]

Sequence
Annotation

Feature key	Position(s)	Length	Description
Polypeptide chain	1 - 1203	1203	Potassium/sodium hyperpolarization- /FTId=PRO_0000054117.
Topological domain	1 - 266	266	Cytoplasmic (Potential).
Topological domain	288 - 293	6	Extracellular (Potential).
Topological domain	315 - 340	26	Cytoplasmic (Potential).
Topological domain	362 - 368	7	Extracellular (Potential).
Topological domain	390 - 420	31	Cytoplasmic (Potential).
Topological domain	442 - 464	23	Extracellular (Potential).
Topological domain	487 - 496	10	Extracellular (Potential).
Topological domain	518 - 1203	686	Cytoplasmic (Potential).
Transmembrane region	267 - 287	21	Helical; Name=Segment S1; (Potential).
Transmembrane region	294 - 314	21	Helical; Name=Segment S2; (Potential).
Transmembrane region	341 - 361	21	Helical; Name=Segment S3; (Potential).
Transmembrane region	369 - 389	21	Helical; Voltage-sensor; Name=Segment S4;
Transmembrane region	421 - 441	21	Helical; Name=Segment S5; (Potential).
Transmembrane region	497 - 517	21	Helical; Name=Segment S6; (Potential).
Located in a membrane without crossing it	465 - 486	22	Pore-forming; Name=Segment H5;
Nucleotide phosphate-binding region	595 - 710	116	cAMP.
Region	209 - 260	52	Involved in subunit assembly (By
Compositionally biased region	924 - 1076	153	Pro-rich.
Posttranslational modification of a residue	935	1	Phosphoserine (By similarity).
Glycosylation site	458	1	N-linked (GlcNAc...) (Potential).
Natural variance	553	1	D -> N (in a patient with cardiac /FTId=VAR_026534.
Natural variance	672	1	S -> R (in SSS2; does not affect cAMP- /FTId=VAR_026535.
Different sources report differing sequences	110	1	S -> T (in Ref. 2; CAB52754).
Helix	522 - 540	19
Helix	545 - 559	15
Helix	566 - 569	4
Helix	575 - 585	11
Helix	587 - 591	5
Helix	594 - 597	4
Helix	601 - 608	8
Helix	661 - 665	5
Helix	686 - 695	10
Helix	697 - 699	3
Helix	700 - 712	13
Strand	612 - 616	5
Strand	621 - 623	3
Strand	631 - 637	7
Strand	639 - 643	5
Strand	650 - 652	3
Strand	670 - 685	16

Protein-protein
Interaction
Databases

DIP
IntAct	Q9Y3Q4
MINT	MINT-7241595
STRING	Q9Y3Q4

Binary Interactions

With	Entry	#Exp.	IntAct
ABL1	P00519	1	EBI-1753521, EBI-375543
FYN	P06241	1	EBI-1753521, EBI-515315

Enzyme and Pathway Databases

Pathway Interaction DB
Reactome

Phylogenomic Database

HOVERGEN	HBG039490
InParanoid	Q9Y3Q4
OMA	CEQPSAD
OrthoDB	EOG46Q6S8

Proteomics
Database (PRIDE)

Q9Y3Q4

Comparative
Toxicogenomics
Database (CTD)

10021

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