HCN4

Protein identityUniProt · HPA

UniProt accession

Q9Y3Q4

Gene

HCN4

Ensembl

ENSG00000138622

Chromosome

15

Canonical length

1203 aa

Protein class

Disease related genes, Human disease related genes, Potential drug targets, Predicted membrane proteins, Transporters, Voltage-gated ion channels

Quaternary structure

Homotetramer

OverviewNCBI Gene

This gene encodes a member of the hyperpolarization-activated cyclic nucleotide-gated potassium channels. The encoded protein shows slow kinetics of activation and inactivation, and is necessary for the cardiac pacemaking process. This channel may also mediate responses to sour stimuli. Mutations in this gene have been linked to sick sinus syndrome 2, also known as atrial fibrillation with bradyarrhythmia or familial sinus bradycardia. Two pseudogenes have been identified on chromosome 15. [provided by RefSeq, Oct 2008]

Canonical amino-acid sequenceUniProt

1203 residues, UniProt reviewed canonical sequence.

>Q9Y3Q4|HCN4
     1  MDKLPPSMRK RLYSLPQQVG AKAWIMDEEE DAEEEGAGGR QDPSRRSIRL RPLPSPSPSA
    61  AAGGTESRSS ALGAADSEGP ARGAGKSSTN GDCRRFRGSL ASLGSRGGGS GGTGSGSSHG
   121  HLHDSAEERR LIAEGDASPG EDRTPPGLAA EPERPGASAQ PAASPPPPQQ PPQPASASCE
   181  QPSVDTAIKV EGGAAAGDQI LPEAEVRLGQ AGFMQRQFGA MLQPGVNKFS LRMFGSQKAV
   241  EREQERVKSA GFWIIHPYSD FRFYWDLTML LLMVGNLIII PVGITFFKDE NTTPWIVFNV
   301  VSDTFFLIDL VLNFRTGIVV EDNTEIILDP QRIKMKYLKS WFMVDFISSI PVDYIFLIVE
   361  TRIDSEVYKT ARALRIVRFT KILSLLRLLR LSRLIRYIHQ WEEIFHMTYD LASAVVRIVN
   421  LIGMMLLLCH WDGCLQFLVP MLQDFPDDCW VSINNMVNNS WGKQYSYALF KAMSHMLCIG
   481  YGRQAPVGMS DVWLTMLSMI VGATCYAMFI GHATALIQSL DSSRRQYQEK YKQVEQYMSF
   541  HKLPPDTRQR IHDYYEHRYQ GKMFDEESIL GELSEPLREE IINFNCRKLV ASMPLFANAD
   601  PNFVTSMLTK LRFEVFQPGD YIIREGTIGK KMYFIQHGVV SVLTKGNKET KLADGSYFGE
   661  ICLLTRGRRT ASVRADTYCR LYSLSVDNFN EVLEEYPMMR RAFETVALDR LDRIGKKNSI
   721  LLHKVQHDLN SGVFNYQENE IIQQIVQHDR EMAHCAHRVQ AAASATPTPT PVIWTPLIQA
   781  PLQAAAATTS VAIALTHHPR LPAAIFRPPP GSGLGNLGAG QTPRHLKRLQ SLIPSALGSA
   841  SPASSPSQVD TPSSSSFHIQ QLAGFSAPAG LSPLLPSSSS SPPPGACGSP SAPTPSAGVA
   901  ATTIAGFGHF HKALGGSLSS SDSPLLTPLQ PGARSPQAAQ PSPAPPGARG GLGLPEHFLP
   961  PPPSSRSPSS SPGQLGQPPG ELSLGLATGP LSTPETPPRQ PEPPSLVAGA SGGASPVGFT
  1021  PRGGLSPPGH SPGPPRTFPS APPRASGSHG SLLLPPASSP PPPQVPQRRG TPPLTPGRLT
  1081  QDLKLISASQ PALPQDGAQT LRRASPHSSG ESMAAFPLFP RAGGGSGGSG SSGGLGPPGR
  1141  PYGAIPGQHV TLPRKTSSGS LPPPLSLFGA RATSSGGPPL TAGPQREPGA RPEPVRSKLP
  1201  SNL

LocalizationUniProt · AlphaFold · HPA

Whether an antibody against HCN4 can act on the native protein depends on physical access: surface and secreted proteins are reachable by circulating antibodies, intracellular proteins usually are not.

Antibody reachability

Cell surface

Secreted

No

Transmembrane segments

6

Mean surface accessibility (rSASA)

0.53

Highest tissue expression

8.2 nTPM

Expression across tissuesHPA

DiseaseUniProt · ClinVar · IEDB · PubMed

Four sources answering four different questions about HCN4.

Disease | AllUniProt

Conditions HCN4 is implicated in, by any mechanism.

• Sick sinus syndrome 2 (SSS2) MIM:163800
• Brugada syndrome 8 (BRGDA8) MIM:613123
• Epilepsy, idiopathic generalized 18 (EIG18) MIM:619521

Disease | GeneticClinVar

21 pathogenic / likely-pathogenic of 2,256 ClinVar records.

Conditions with pathogenic or likely-pathogenic variants.

• Brugada syndrome 8
• Sick sinus syndrome 2, autosomal dominant
• Cardiovascular phenotype
• Left ventricular noncompaction cardiomyopathy
• HCN4-related disorder

Genetic constraint and essentialitygnomAD · DepMap

Does the body need this protein intact? Low LOEUF or a strong DepMap dependency means loss or blockade of the protein is likely to be felt.

gnomAD LOEUF (loss-of-function intolerance)

0.24

gnomAD pLI

1

gnomAD missense Z

2.75

DepMap mean gene effect

0.01

DepMap dependency class

selective

Cancer expressionTCGA

Across TCGA tumor cohorts, this protein is over-expressed in roughly 3% of surveyed tumor types (aggregate summary; per-cohort expression, alteration, and survival load in the interactive view).

OntologyGO

Biological processes

• blood circulation
• cellular response to cAMP
• cellular response to cGMP
• membrane depolarization during cardiac muscle cell action potential
• membrane depolarization during SA node cell action potential
• monoatomic cation transport
• muscle contraction
• potassium ion import across plasma membrane
• potassium ion transmembrane transport
• regulation of cardiac muscle cell action potential involved in regulation of contraction
• regulation of cardiac muscle contraction
• regulation of heart rate
• regulation of heart rate by cardiac conduction
• regulation of membrane depolarization
• regulation of membrane potential
• regulation of SA node cell action potential
• SA node cell action potential
• sinoatrial node development
• sodium ion import across plasma membrane
• sodium ion transmembrane transport

Molecular functions

• cAMP binding
• identical protein binding
• intracellularly cAMP-activated cation channel activity
• voltage-gated potassium channel activity
• voltage-gated sodium channel activity
• voltage-gated potassium channel activity involved in SA node cell action potential depolarization

Cellular components

• axon
• dendrite
• HCN channel complex
• perinuclear region of cytoplasm
• plasma membrane

Protein domainsUniProt · Pfam · InterPro

• Cyclic nucleotide-binding domain
• Potassium channel, voltage-dependent, EAG/ELK/ERG-like
• Ion transport domain
• Ion transport N-terminal
• RmlC-like jelly roll fold
• Cyclic nucleotide-binding, conserved site
• Cyclic nucleotide-binding domain superfamily
• Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel
• Cyclic nucleotide-binding domain
• Ion transport protein
• Ion transport protein N-terminal

KeywordsUniProt

• Brugada syndrome
• cAMP
• cAMP-binding
• Cell membrane
• Epilepsy
• Glycoprotein
• Ion channel
• Ion transport
• Ligand-gated ion channel
• Membrane
• Nucleotide-binding
• Phosphoprotein
• Potassium
• Potassium channel
• Potassium transport
• Sodium
• Sodium channel
• Sodium transport
• Transmembrane
• Transmembrane helix
• Transport
• Voltage-gated channel

InteractionsUniProt · HPA

Protein binding partners of HCN4 in the human serome: UniProt-annotated complex subunits plus reported interactors. Each links to its own Seroatlas record.

• IRAG1
• IRAG2
• HCN1