O15554 · KCNN4_HUMAN
- ProteinIntermediate conductance calcium-activated potassium channel protein 4
- GeneKCNN4
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids427 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Intermediate conductance calcium-activated potassium channel that mediates the voltage-independent transmembrane transfer of potassium across the cell membrane through a constitutive interaction with calmodulin which binds the intracellular calcium allowing its opening (PubMed:10026195, PubMed:10961988, PubMed:11425865, PubMed:15831468, PubMed:17157250, PubMed:18796614, PubMed:26148990, PubMed:9326665, PubMed:9380751, PubMed:9407042).
The current is characterized by a voltage-independent activation, an intracellular calcium concentration increase-dependent activation and a single-channel conductance of about 25 picosiemens (PubMed:9326665, PubMed:9380751, PubMed:9407042).
Also presents an inwardly rectifying current, thus reducing its already small outward conductance of potassium ions, which is particularly the case when the membrane potential displays positive values, above + 20 mV (PubMed:9326665, PubMed:9380751, PubMed:9407042).
Controls calcium influx during vascular contractility by being responsible of membrane hyperpolarization induced by vasoactive factors in proliferative vascular smooth muscle cell types (By similarity).
Following calcium influx, the consecutive activation of KCNN4 channel leads to a hyperpolarization of the cell membrane potential and hence an increase of the electrical driving force for further calcium influx promoting sustained calcium entry in response to stimulation with chemotactic peptides (PubMed:26418693).
Required for maximal calcium influx and proliferation during the reactivation of naive T-cells (PubMed:17157250, PubMed:18796614).
Plays a role in the late stages of EGF-induced macropinocytosis through activation by PI3P (PubMed:24591580).
The current is characterized by a voltage-independent activation, an intracellular calcium concentration increase-dependent activation and a single-channel conductance of about 25 picosiemens (PubMed:9326665, PubMed:9380751, PubMed:9407042).
Also presents an inwardly rectifying current, thus reducing its already small outward conductance of potassium ions, which is particularly the case when the membrane potential displays positive values, above + 20 mV (PubMed:9326665, PubMed:9380751, PubMed:9407042).
Controls calcium influx during vascular contractility by being responsible of membrane hyperpolarization induced by vasoactive factors in proliferative vascular smooth muscle cell types (By similarity).
Following calcium influx, the consecutive activation of KCNN4 channel leads to a hyperpolarization of the cell membrane potential and hence an increase of the electrical driving force for further calcium influx promoting sustained calcium entry in response to stimulation with chemotactic peptides (PubMed:26418693).
Required for maximal calcium influx and proliferation during the reactivation of naive T-cells (PubMed:17157250, PubMed:18796614).
Plays a role in the late stages of EGF-induced macropinocytosis through activation by PI3P (PubMed:24591580).
Catalytic activity
- K+(in) = K+(out)
Activity regulation
The channel is inhibited by clotrimazole and charybdotoxin but is insensitive to apamin.
GO annotations
Keywords
- Molecular function
- Biological process
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameIntermediate conductance calcium-activated potassium channel protein 4
- Short namesSKCa 4; SKCa4; hSK4
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionO15554
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Cell membrane ; Multi-pass membrane protein
Note: Targeted to membrane ruffles after EGF stimulation.
Features
Showing features for transmembrane, intramembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Transmembrane | 29-49 | Helical; Name=Segment S1 | ||||
Sequence: ALVLAGTGIGLMVLHAEMLWF | ||||||
Transmembrane | 59-79 | Helical; Name=Segment S2 | ||||
Sequence: FLVKCTISISTFLLLCLIVAF | ||||||
Transmembrane | 108-128 | Helical; Name=Segment S3 | ||||
Sequence: IVLELVVCGLHPAPVRGPPCV | ||||||
Transmembrane | 143-163 | Helical; Name=Segment S4 | ||||
Sequence: GFLGQGEALLSLAMLLRLYLV | ||||||
Transmembrane | 207-227 | Helical; Name=Segment S5 | ||||
Sequence: LLLGLTLGLWLTTAWVLSVAE | ||||||
Intramembrane | 241-261 | Pore-forming; Name=Segment H5 | ||||
Sequence: LWLIPITFLTIGYGDVVPGTM | ||||||
Transmembrane | 265-285 | Helical; Name=Segment S6 | ||||
Sequence: IVCLCTGVMGVCCTALLVAVV |
Keywords
- Cellular component
Disease & Variants
Involvement in disease
Dehydrated hereditary stomatocytosis 2 (DHS2)
- Note
- DescriptionAn autosomal dominant hemolytic anemia characterized by primary erythrocyte dehydration. Erythrocytes exhibit decreased total cation and potassium content that are not accompanied by a proportional net gain of sodium and water. Affected individuals typically manifest mild to moderate compensated hemolytic anemia, with an increased erythrocyte mean corpuscular hemoglobin concentration and a decreased osmotic fragility, both of which reflect cellular dehydration. Their red cells exhibit a panel of various shape abnormalities such as elliptocytes, hemighosts, schizocytes, and very rare stomatocytic cells. Complications such as splenomegaly and cholelithiasis, resulting from increased red cell trapping in the spleen and elevated bilirubin levels, respectively, may occur.
- See alsoMIM:616689
Natural variants in DHS2
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_074485 | 282 | V>E | in DHS2; dbSNP:rs1057519077 | |
VAR_074486 | 282 | V>M | in DHS2; dbSNP:rs1057519076 | |
VAR_074487 | 352 | R>H | in DHS2; no effect on plasma membrane localization; increases calcium-activated potassium channel activity; dbSNP:rs774455945 |
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 250 | Loss of sensitivity to triarylmethanes. | ||||
Sequence: T → S | ||||||
Mutagenesis | 275 | Loss of sensitivity to triarylmethanes. | ||||
Sequence: V → A | ||||||
Natural variant | VAR_074485 | 282 | in DHS2; dbSNP:rs1057519077 | |||
Sequence: V → E | ||||||
Natural variant | VAR_074486 | 282 | in DHS2; dbSNP:rs1057519076 | |||
Sequence: V → M | ||||||
Natural variant | VAR_074487 | 352 | in DHS2; no effect on plasma membrane localization; increases calcium-activated potassium channel activity; dbSNP:rs774455945 | |||
Sequence: R → H |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 471 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain, modified residue (large scale data), modified residue.
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000155017 | 1-427 | UniProt | Intermediate conductance calcium-activated potassium channel protein 4 | |||
Sequence: MGGDLVLGLGALRRRKRLLEQEKSLAGWALVLAGTGIGLMVLHAEMLWFGGCSWALYLFLVKCTISISTFLLLCLIVAFHAKEVQLFMTDNGLRDWRVALTGRQAAQIVLELVVCGLHPAPVRGPPCVQDLGAPLTSPQPWPGFLGQGEALLSLAMLLRLYLVPRAVLLRSGVLLNASYRSIGALNQVRFRHWFVAKLYMNTHPGRLLLGLTLGLWLTTAWVLSVAERQAVNATGHLSDTLWLIPITFLTIGYGDVVPGTMWGKIVCLCTGVMGVCCTALLVAVVARKLEFNKAEKHVHNFMMDIQYTKEMKESAARVLQEAWMFYKHTRRKESHAARRHQRKLLAAINAFRQVRLKHRKLREQVNSMVDISKMHMILYDLQQNLSSSHRALEKQIDTLAGKLDALTELLSTALGPRQLPEPSQQSK | |||||||
Modified residue (large scale data) | 178 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 358 | UniProt | Phosphohistidine | ||||
Sequence: H |
Post-translational modification
Phosphorylation at His-358 by NDKB activates the intermediate conductance calcium-activated potassium channel activity, and conversely it's dephosphorylation by PHPT1 inhibits this activity.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Widely expressed in non-excitable tissues.
Induction
Up-regulated by phorbol myristate acetate (PMA) and phytohemagglutinin (PHA) in T-cells.
Gene expression databases
Organism-specific databases
Interaction
Subunit
Homodimer (PubMed:29953543).
Homotetramer (PubMed:29724949).
Heterotetramer of potassium channel proteins (Probable). Interacts with MTMR6; this interaction leads to selective dephosphorylation of PI3P in a lipid microdomain adjacent to KCNN4, resulting in a decrease of intermediate conductance calcium-activated potassium channel activity (PubMed:15831468).
Interacts (via the C-tail domain) with CALM1; the calmodulin binding is constitutive, does not require calcium and mediates calcium-dependent gating and four calmodulin molecules bind to one channel tetramer (PubMed:10026195).
Homotetramer (PubMed:29724949).
Heterotetramer of potassium channel proteins (Probable). Interacts with MTMR6; this interaction leads to selective dephosphorylation of PI3P in a lipid microdomain adjacent to KCNN4, resulting in a decrease of intermediate conductance calcium-activated potassium channel activity (PubMed:15831468).
Interacts (via the C-tail domain) with CALM1; the calmodulin binding is constitutive, does not require calcium and mediates calcium-dependent gating and four calmodulin molecules bind to one channel tetramer (PubMed:10026195).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | O15554 | BIK Q13323 | 3 | EBI-2924473, EBI-700794 | |
BINARY | O15554 | CALM3 P0DP25 | 2 | EBI-2924473, EBI-397435 | |
BINARY | O15554 | CFTR P13569 | 5 | EBI-2924473, EBI-349854 | |
BINARY | O15554 | CNIH3 Q8TBE1 | 3 | EBI-2924473, EBI-12208021 | |
BINARY | O15554 | FXYD3 Q14802-3 | 3 | EBI-2924473, EBI-12175685 | |
BINARY | O15554 | GPR152 Q8TDT2 | 3 | EBI-2924473, EBI-13345167 | |
BINARY | O15554 | PHPT1 Q9NRX4 | 2 | EBI-2924473, EBI-740955 | |
BINARY | O15554 | PMP22 Q01453 | 3 | EBI-2924473, EBI-2845982 | |
BINARY | O15554 | SLC30A2 Q9BRI3 | 3 | EBI-2924473, EBI-8644112 | |
BINARY | O15554 | STX1B P61266 | 3 | EBI-2924473, EBI-9071709 |
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for region.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 286-347 | Calmodulin-binding | ||||
Sequence: ARKLEFNKAEKHVHNFMMDIQYTKEMKESAARVLQEAWMFYKHTRRKESHAARRHQRKLLAA |
Domain
Transmembrane helices S5 and S6 form the ion channel pore, which is surrounded bymembrane embedded helices S1 to S4 (PubMed:29724949).
The S4-S5 linker, which contains two distinct helices, undergoes conformational changes upon calmodulin binding to open the channel pore (PubMed:29724949).
The S4-S5 linker, which contains two distinct helices, undergoes conformational changes upon calmodulin binding to open the channel pore (PubMed:29724949).
Sequence similarities
Belongs to the potassium channel KCNN family. KCa3.1/KCNN4 subfamily.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length427
- Mass (Da)47,696
- Last updated1998-01-01 v1
- Checksum23F9AF66609B410F
Computationally mapped potential isoform sequences
There are 4 potential isoforms mapped to this entry
Features
Showing features for sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 66 | in Ref. 6; AAK81862 | ||||
Sequence: S → G |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF000972 EMBL· GenBank· DDBJ | AAB82739.1 EMBL· GenBank· DDBJ | mRNA | ||
AF022150 EMBL· GenBank· DDBJ | AAC23541.1 EMBL· GenBank· DDBJ | mRNA | ||
AF022797 EMBL· GenBank· DDBJ | AAC51913.1 EMBL· GenBank· DDBJ | mRNA | ||
AF033021 EMBL· GenBank· DDBJ | AAC36804.1 EMBL· GenBank· DDBJ | mRNA | ||
AF305735 EMBL· GenBank· DDBJ | AAG26917.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF305731 EMBL· GenBank· DDBJ | AAG26917.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF305732 EMBL· GenBank· DDBJ | AAG26917.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF305733 EMBL· GenBank· DDBJ | AAG26917.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF305734 EMBL· GenBank· DDBJ | AAG26917.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF395661 EMBL· GenBank· DDBJ | AAK81862.1 EMBL· GenBank· DDBJ | mRNA | ||
BT007426 EMBL· GenBank· DDBJ | AAP36094.1 EMBL· GenBank· DDBJ | mRNA | ||
CH471126 EMBL· GenBank· DDBJ | EAW57230.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC015337 EMBL· GenBank· DDBJ | AAH15337.1 EMBL· GenBank· DDBJ | mRNA | ||
AF053403 EMBL· GenBank· DDBJ | AAC35281.1 EMBL· GenBank· DDBJ | mRNA |