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Protein

Potassium voltage-gated channel subfamily A member 5

Gene

KCNA5

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane. Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel (PubMed:12130714). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation (PubMed:12130714). Homotetrameric channels display rapid activation and slow inactivation (PubMed:8505626, PubMed:12130714). May play a role in regulating the secretion of insulin in normal pancreatic islets. Isoform 2 exhibits a voltage-dependent recovery from inactivation and an excessive cumulative inactivation (PubMed:11524461).3 Publications

GO - Molecular functioni

  • alpha-actinin binding Source: BHF-UCL
  • delayed rectifier potassium channel activity Source: UniProtKB
  • outward rectifier potassium channel activity Source: BHF-UCL
  • potassium channel inhibitor activity Source: Ensembl
  • protein kinase binding Source: BHF-UCL
  • scaffold protein binding Source: BHF-UCL
  • voltage-gated potassium channel activity involved in atrial cardiac muscle cell action potential repolarization Source: BHF-UCL
  • voltage-gated potassium channel activity involved in bundle of His cell action potential repolarization Source: BHF-UCL
  • voltage-gated potassium channel activity involved in SA node cell action potential repolarization Source: BHF-UCL

GO - Biological processi

  • atrial cardiac muscle cell action potential Source: BHF-UCL
  • membrane hyperpolarization Source: BHF-UCL
  • membrane repolarization during atrial cardiac muscle cell action potential Source: BHF-UCL
  • membrane repolarization during bundle of His cell action potential Source: BHF-UCL
  • membrane repolarization during SA node cell action potential Source: BHF-UCL
  • negative regulation of cytosolic calcium ion concentration Source: Ensembl
  • negative regulation of potassium ion transport Source: Ensembl
  • Notch signaling pathway Source: Ensembl
  • positive regulation of G1/S transition of mitotic cell cycle Source: Ensembl
  • positive regulation of myoblast proliferation Source: Ensembl
  • potassium ion export Source: BHF-UCL
  • potassium ion homeostasis Source: Ensembl
  • potassium ion transmembrane transport Source: UniProtKB
  • potassium ion transport Source: MGI
  • protein homooligomerization Source: InterPro
  • regulation of atrial cardiac muscle cell membrane repolarization Source: BHF-UCL
  • regulation of heart rate by cardiac conduction Source: BHF-UCL
  • regulation of insulin secretion Source: BHF-UCL
  • regulation of membrane potential Source: BHF-UCL
  • regulation of potassium ion transport Source: BHF-UCL
  • regulation of vasoconstriction Source: Ensembl
  • response to hydrogen peroxide Source: Ensembl
  • response to hyperoxia Source: Ensembl
  • response to hypoxia Source: Ensembl
  • response to mechanical stimulus Source: Ensembl
  • response to organic substance Source: Ensembl

Keywordsi

Molecular functionIon channel, Potassium channel, Voltage-gated channel
Biological processIon transport, Potassium transport, Transport
LigandPotassium

Enzyme and pathway databases

ReactomeiR-HSA-1296072 Voltage gated Potassium channels

Protein family/group databases

TCDBi1.A.1.2.4 the voltage-gated ion channel (vic) superfamily

Names & Taxonomyi

Protein namesi
Recommended name:
Potassium voltage-gated channel subfamily A member 5
Alternative name(s):
HPCN1
Voltage-gated potassium channel HK2
Voltage-gated potassium channel subunit Kv1.5
Gene namesi
Name:KCNA5
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

EuPathDBiHostDB:ENSG00000130037.4
HGNCiHGNC:6224 KCNA5
MIMi176267 gene
neXtProtiNX_P22460

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 247CytoplasmicBy similarityAdd BLAST247
Transmembranei248 – 269Helical; Name=Segment S1By similarityAdd BLAST22
Topological domaini270 – 323ExtracellularBy similarityAdd BLAST54
Transmembranei324 – 345Helical; Name=Segment S2By similarityAdd BLAST22
Topological domaini346 – 356CytoplasmicBy similarityAdd BLAST11
Transmembranei357 – 377Helical; Name=Segment S3By similarityAdd BLAST21
Topological domaini378 – 395ExtracellularBy similarityAdd BLAST18
Transmembranei396 – 416Helical; Voltage-sensor; Name=Segment S4By similarityAdd BLAST21
Topological domaini417 – 431CytoplasmicBy similarityAdd BLAST15
Transmembranei432 – 453Helical; Name=Segment S5By similarityAdd BLAST22
Topological domaini454 – 467ExtracellularBy similarityAdd BLAST14
Intramembranei468 – 479Helical; Name=Pore helixBy similarityAdd BLAST12
Intramembranei480 – 487By similarity8
Topological domaini488 – 494ExtracellularBy similarity7
Transmembranei495 – 523Helical; Name=Segment S6By similarityAdd BLAST29
Topological domaini524 – 613CytoplasmicBy similarityAdd BLAST90

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Involvement in diseasei

Atrial fibrillation, familial, 7 (ATFB7)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure.
See also OMIM:612240

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi15T → A: Loss of DLG1 effect on channel current. 1 Publication1
Mutagenesisi220I → N: Reduces sumoylation; when associated with N-535. 1 Publication1
Mutagenesisi221K → R: Abolishes sumoylation; when associated with R-536. 1 Publication1
Mutagenesisi535L → N: Reduces sumoylation; when associated with N-220. 1 Publication1
Mutagenesisi536K → R: Abolishes sumoylation; when associated with R-221. 1 Publication1

Keywords - Diseasei

Atrial fibrillation

Organism-specific databases

DisGeNETi3741
MalaCardsiKCNA5
MIMi612240 phenotype
OpenTargetsiENSG00000130037
Orphaneti334 Familial atrial fibrillation
PharmGKBiPA208

Chemistry databases

ChEMBLiCHEMBL4306
DrugBankiDB06637 Dalfampridine
GuidetoPHARMACOLOGYi542

Polymorphism and mutation databases

BioMutaiKCNA5
DMDMi146345443

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000539851 – 613Potassium voltage-gated channel subfamily A member 5Add BLAST613

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Cross-linki221Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)1 Publication
Lipidationi346S-palmitoyl cysteineSequence analysis1
Cross-linki536Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)1 Publication
Modified residuei557Phosphoserine; by PKASequence analysis1

Post-translational modificationi

Sumoylated on Lys-221, and Lys-536, preferentially with SUMO3. Sumoylation regulates the voltage sensitivity of the channel.1 Publication

Keywords - PTMi

Isopeptide bond, Lipoprotein, Palmitate, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiP22460
PeptideAtlasiP22460
PRIDEiP22460

PTM databases

iPTMnetiP22460
PhosphoSitePlusiP22460
SwissPalmiP22460

Expressioni

Tissue specificityi

Pancreatic islets and insulinoma.

Gene expression databases

BgeeiENSG00000130037
CleanExiHS_KCNA5
GenevisibleiP22460 HS

Organism-specific databases

HPAiCAB022562
HPA021516

Interactioni

Subunit structurei

Homotetramer and heterotetramer of potassium channel proteins. Interacts with DLG1, which enhances channel currents. Forms a ternary complex with DLG1 and CAV3 (By similarity). Interacts with KCNAB1 (PubMed:12130714). Interacts with UBE2I (PubMed:17261810).By similarity5 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • alpha-actinin binding Source: BHF-UCL
  • protein kinase binding Source: BHF-UCL
  • scaffold protein binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi109943, 58 interactors
DIPiDIP-42010N
IntActiP22460, 10 interactors
MINTiP22460
STRINGi9606.ENSP00000252321

Chemistry databases

BindingDBiP22460

Structurei

3D structure databases

ProteinModelPortaliP22460
SMRiP22460
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati61 – 711Add BLAST11
Repeati72 – 822Add BLAST11

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni61 – 822 X 11 AA tandem repeat of D-[SP]-G-V-R-P-L-P-P-L-PAdd BLAST22
Regioni418 – 431S4-S5 linkerBy similarityAdd BLAST14

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi480 – 485Selectivity filterBy similarity6
Motifi611 – 613PDZ-bindingBy similarity3

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi94 – 99Poly-Glu6
Compositional biasi382 – 387Poly-Gly6

Domaini

The amino terminus may be important in determining the rate of inactivation of the channel while the C-terminal PDZ-binding motif may play a role in modulation of channel activity and/or targeting of the channel to specific subcellular compartments.
The transmembrane segment S4 functions as voltage-sensor and is characterized by a series of positively charged amino acids at every third position. Channel opening and closing is effected by a conformation change that affects the position and orientation of the voltage-sensor paddle formed by S3 and S4 within the membrane. A transmembrane electric field that is positive inside would push the positively charged S4 segment outwards, thereby opening the pore, while a field that is negative inside would pull the S4 segment inwards and close the pore. Changes in the position and orientation of S4 are then transmitted to the activation gate formed by the inner helix bundle via the S4-S5 linker region.By similarity

Sequence similaritiesi

Keywords - Domaini

Repeat, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG1545 Eukaryota
COG1226 LUCA
GeneTreeiENSGT00760000118846
HOGENOMiHOG000231015
HOVERGENiHBG052230
InParanoidiP22460
KOiK04878
OMAiLPRNEFQ
OrthoDBiEOG091G10NU
PhylomeDBiP22460
TreeFamiTF313103

Family and domain databases

Gene3Di1.20.120.350, 1 hit
InterProiView protein in InterPro
IPR000210 BTB/POZ_dom
IPR005821 Ion_trans_dom
IPR003968 K_chnl_volt-dep_Kv
IPR003972 K_chnl_volt-dep_Kv1
IPR004052 K_chnl_volt-dep_Kv1.5
IPR011333 SKP1/BTB/POZ_sf
IPR003131 T1-type_BTB
IPR028325 VG_K_chnl
IPR027359 Volt_channel_dom_sf
PANTHERiPTHR11537 PTHR11537, 1 hit
PfamiView protein in Pfam
PF02214 BTB_2, 1 hit
PF00520 Ion_trans, 1 hit
PRINTSiPR00169 KCHANNEL
PR01512 KV15CHANNEL
PR01491 KVCHANNEL
PR01496 SHAKERCHANEL
SMARTiView protein in SMART
SM00225 BTB, 1 hit
SUPFAMiSSF54695 SSF54695, 1 hit

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P22460-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MEIALVPLEN GGAMTVRGGD EARAGCGQAT GGELQCPPTA GLSDGPKEPA
60 70 80 90 100
PKGRGAQRDA DSGVRPLPPL PDPGVRPLPP LPEELPRPRR PPPEDEEEEG
110 120 130 140 150
DPGLGTVEDQ ALGTASLHHQ RVHINISGLR FETQLGTLAQ FPNTLLGDPA
160 170 180 190 200
KRLRYFDPLR NEYFFDRNRP SFDGILYYYQ SGGRLRRPVN VSLDVFADEI
210 220 230 240 250
RFYQLGDEAM ERFREDEGFI KEEEKPLPRN EFQRQVWLIF EYPESSGSAR
260 270 280 290 300
AIAIVSVLVI LISIITFCLE TLPEFRDERE LLRHPPAPHQ PPAPAPGANG
310 320 330 340 350
SGVMAPPSGP TVAPLLPRTL ADPFFIVETT CVIWFTFELL VRFFACPSKA
360 370 380 390 400
GFSRNIMNII DVVAIFPYFI TLGTELAEQQ PGGGGGGQNG QQAMSLAILR
410 420 430 440 450
VIRLVRVFRI FKLSRHSKGL QILGKTLQAS MRELGLLIFF LFIGVILFSS
460 470 480 490 500
AVYFAEADNQ GTHFSSIPDA FWWAVVTMTT VGYGDMRPIT VGGKIVGSLC
510 520 530 540 550
AIAGVLTIAL PVPVIVSNFN YFYHRETDHE EPAVLKEEQG TQSQGPGLDR
560 570 580 590 600
GVQRKVSGSR GSFCKAGGTL ENADSARRGS CPLEKCNVKA KSNVDLRRSL
610
YALCLDTSRE TDL
Length:613
Mass (Da):67,228
Last modified:May 1, 2007 - v4
Checksum:iA5B02B27F8396E3D
GO
Isoform 2 (identifier: P22460-2) [UniParc]FASTAAdd to basket
Also known as: Short

The sequence of this isoform differs from the canonical sequence as follows:
     1-209: Missing.

Show »
Length:404
Mass (Da):44,427
Checksum:i75826108B430EAC1
GO

Sequence cautioni

The sequence AAA60146 differs from that shown. Reason: Frameshift at position 579.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti55Missing in AAA61276 (PubMed:2001794).Curated1
Sequence conflicti138L → Q in AAA36422 (PubMed:1986382).Curated1
Sequence conflicti154R → P in AAA61276 (PubMed:2001794).Curated1
Sequence conflicti154R → P in AAA36422 (PubMed:1986382).Curated1
Sequence conflicti187 – 188RP → G in AAA61276 (PubMed:2001794).Curated2
Sequence conflicti214R → G in AAA36422 (PubMed:1986382).Curated1
Sequence conflicti228P → V in AAA36422 (PubMed:1986382).Curated1
Sequence conflicti282L → V in AAA60146 (PubMed:1349297).Curated1
Sequence conflicti307P → A in AAA61276 (PubMed:2001794).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07960242L → H Found in a patient with pulmonary arterial hypertension; unknown pathological significance. 1 Publication1
Natural variantiVAR_07960385L → M1 Publication1
Natural variantiVAR_079604114T → P Found in a patient with pulmonary arterial hypertension; unknown pathological significance. 1 Publication1
Natural variantiVAR_079605170P → R Found in a patient with pulmonary arterial hypertension; unknown pathological significance. 1 Publication1
Natural variantiVAR_079606184R → P Found in a patient with pulmonary arterial hypertension; unknown pathological significance. 1 Publication1
Natural variantiVAR_053856228P → S. Corresponds to variant dbSNP:rs1056464Ensembl.1
Natural variantiVAR_035770300G → S in a breast cancer sample; somatic mutation. 1 PublicationCorresponds to variant dbSNP:rs148708451EnsemblClinVar.1
Natural variantiVAR_054786578R → K. Corresponds to variant dbSNP:rs12720445EnsemblClinVar.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0371101 – 209Missing in isoform 2. CuratedAdd BLAST209

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M60451 mRNA Translation: AAA61276.1
M55513 mRNA Translation: AAA36422.1
M83254 mRNA Translation: AAA60146.1 Frameshift.
BC096357 mRNA Translation: AAH96357.1
BC096358 mRNA Translation: AAH96358.3
BC099665 mRNA Translation: AAH99665.3
BC099666 mRNA Translation: AAH99666.3
CCDSiCCDS8536.1 [P22460-1]
PIRiA56031
RefSeqiNP_002225.2, NM_002234.3 [P22460-1]
UniGeneiHs.150208
Hs.741439

Genome annotation databases

EnsembliENST00000252321; ENSP00000252321; ENSG00000130037 [P22460-1]
GeneIDi3741
KEGGihsa:3741
UCSCiuc001qni.5 human [P22460-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiKCNA5_HUMAN
AccessioniPrimary (citable) accession number: P22460
Secondary accession number(s): Q4KKT8
, Q4VAJ1, Q4VAJ2, Q9UDA4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 1, 1991
Last sequence update: May 1, 2007
Last modified: May 23, 2018
This is version 180 of the entry and version 4 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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

Complete proteome, Reference proteome

Documents

  1. Human chromosome 12
    Human chromosome 12: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families

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