P08637 · FCG3A_HUMAN
- ProteinLow affinity immunoglobulin gamma Fc region receptor III-A
- GeneFCGR3A
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids254 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Receptor for the invariable Fc fragment of immunoglobulin gamma (IgG). Optimally activated upon binding of clustered antigen-IgG complexes displayed on cell surfaces, triggers lysis of antibody-coated cells, a process known as antibody-dependent cellular cytotoxicity (ADCC). Does not bind free monomeric IgG, thus avoiding inappropriate effector cell activation in the absence of antigenic trigger (PubMed:11711607, PubMed:21768335, PubMed:22023369, PubMed:24412922, PubMed:25786175, PubMed:25816339, PubMed:28652325, PubMed:8609432, PubMed:9242542).
Mediates IgG effector functions on natural killer (NK) cells. Binds antigen-IgG complexes generated upon infection and triggers NK cell-dependent cytokine production and degranulation to limit viral load and propagation. Involved in the generation of memory-like adaptive NK cells capable to produce high amounts of IFNG and to efficiently eliminate virus-infected cells via ADCC (PubMed:24412922, PubMed:25786175).
Regulates NK cell survival and proliferation, in particular by preventing NK cell progenitor apoptosis (PubMed:29967280, PubMed:9916693).
Fc-binding subunit that associates with CD247 and/or FCER1G adapters to form functional signaling complexes. Following the engagement of antigen-IgG complexes, triggers phosphorylation of immunoreceptor tyrosine-based activation motif (ITAM)-containing adapters with subsequent activation of phosphatidylinositol 3-kinase signaling and sustained elevation of intracellular calcium that ultimately drive NK cell activation. The ITAM-dependent signaling coupled to receptor phosphorylation by PKC mediates robust intracellular calcium flux that leads to production of pro-inflammatory cytokines, whereas in the absence of receptor phosphorylation it mainly activates phosphatidylinositol 3-kinase signaling leading to cell degranulation (PubMed:1825220, PubMed:23024279, PubMed:2532305).
Costimulates NK cells and trigger lysis of target cells independently of IgG binding (PubMed:10318937, PubMed:23006327).
Mediates the antitumor activities of therapeutic antibodies. Upon ligation on monocytes triggers TNFA-dependent ADCC of IgG-coated tumor cells (PubMed:27670158).
Mediates enhanced ADCC in response to afucosylated IgGs (PubMed:34485821).
Mediates IgG effector functions on natural killer (NK) cells. Binds antigen-IgG complexes generated upon infection and triggers NK cell-dependent cytokine production and degranulation to limit viral load and propagation. Involved in the generation of memory-like adaptive NK cells capable to produce high amounts of IFNG and to efficiently eliminate virus-infected cells via ADCC (PubMed:24412922, PubMed:25786175).
Regulates NK cell survival and proliferation, in particular by preventing NK cell progenitor apoptosis (PubMed:29967280, PubMed:9916693).
Fc-binding subunit that associates with CD247 and/or FCER1G adapters to form functional signaling complexes. Following the engagement of antigen-IgG complexes, triggers phosphorylation of immunoreceptor tyrosine-based activation motif (ITAM)-containing adapters with subsequent activation of phosphatidylinositol 3-kinase signaling and sustained elevation of intracellular calcium that ultimately drive NK cell activation. The ITAM-dependent signaling coupled to receptor phosphorylation by PKC mediates robust intracellular calcium flux that leads to production of pro-inflammatory cytokines, whereas in the absence of receptor phosphorylation it mainly activates phosphatidylinositol 3-kinase signaling leading to cell degranulation (PubMed:1825220, PubMed:23024279, PubMed:2532305).
Costimulates NK cells and trigger lysis of target cells independently of IgG binding (PubMed:10318937, PubMed:23006327).
Mediates the antitumor activities of therapeutic antibodies. Upon ligation on monocytes triggers TNFA-dependent ADCC of IgG-coated tumor cells (PubMed:27670158).
Mediates enhanced ADCC in response to afucosylated IgGs (PubMed:34485821).
(Microbial infection) Involved in Dengue virus pathogenesis via antibody-dependent enhancement (ADE) mechanism. Secondary infection with Dengue virus triggers elevated levels of afucosylated non-neutralizing IgG1s with reactivity to viral envelope/E protein. Viral antigen-IgG1 complexes bind with high affinity to FCGR3A, facilitating virus entry in myeloid cells and subsequent viral replication.
Miscellaneous
Encoded by one of two nearly identical genes: FCGR3A (shown here) and FCGR3B which are expressed in a tissue-specific manner. The Phe-203 in III-A determines the transmembrane domains whereas the 'Ser-203' in III-B determines the GPI-anchoring.
FCGR3A in mammals is the true ortholog of FCGR4 in rodents. The FCGR2A-HSPA6-FCGR4-FCGR2B module was duplicated in great apes through non-allelic homologous recombination, giving rise to two FCGR4-type genes and to FCGR2C, a hybrid gene combining FCGR2A and FCGR2B. While FCGR3A kept the original FCGR4 functionality, FCGR3B rapidly evolved and acquired specific features coding for a GPI-anchored receptor.
Features
Showing features for site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Site | 195-196 | Cleavage; by ADAM17 | ||||
Sequence: AV | ||||||
Site | 222 | Important for receptor turnover | ||||
Sequence: D |
GO annotations
Keywords
- Molecular function
- Biological process
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameLow affinity immunoglobulin gamma Fc region receptor III-A
- Short namesIgG Fc receptor III-A
- Alternative names
- CD Antigen Name
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionP08637
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Cell membrane ; Single-pass type I membrane protein
Note: Exists also as a soluble receptor.
Features
Showing features for topological domain, transmembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Topological domain | 17-208 | Extracellular | ||||
Sequence: GMRTEDLPKAVVFLEPQWYRVLEKDSVTLKCQGAYSPEDNSTQWFHNESLISSQASSYFIDAATVDDSGEYRCQTNLSTLSDPVQLEVHIGWLLLQAPRWVFKEEDPIHLRCHSWKNTALHKVTYLQNGKGRKYFHHNSDFYIPKATLKDSGSYFCRGLFGSKNVSSETVNITITQGLAVSTISSFFPPGYQ | ||||||
Transmembrane | 209-229 | Helical | ||||
Sequence: VSFCLVMVLLFAVDTGLYFSV | ||||||
Topological domain | 230-254 | Cytoplasmic | ||||
Sequence: KTNIRSSTRDWKDHKFKWRKDPQDK |
Keywords
- Cellular component
Disease & Variants
Involvement in disease
Immunodeficiency 20 (IMD20)
- Note
- DescriptionA rare autosomal recessive primary immunodeficiency characterized by functional deficiency of NK cells. Affected individuals typically present with severe herpes viral infections, particularly Epstein Barr virus (EBV), and human papillomavirus (HPV).
- See alsoMIM:615707
Natural variants in IMD20
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_008800 | 66 | L>H | in IMD20; loss of interaction with CD2; dbSNP:rs10127939 |
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_008800 | 66 | in IMD20; loss of interaction with CD2; dbSNP:rs10127939 | |||
Sequence: L → H | ||||||
Natural variant | VAR_008799 | 66 | in dbSNP:rs10127939 | |||
Sequence: L → R | ||||||
Natural variant | VAR_058398 | 147 | in dbSNP:rs443082 | |||
Sequence: G → D | ||||||
Natural variant | VAR_058399 | 158 | in dbSNP:rs396716 | |||
Sequence: Y → H | ||||||
Natural variant | VAR_003960 | 176 | shows a higher binding capacity for IgG1, IgG3 and IgG4; dbSNP:rs396991 | |||
Sequence: F → V | ||||||
Mutagenesis | 197 | Impairs receptor shedding. Impairs the detachment of NK cells from opsonized target cells upon sequential activation. | ||||
Sequence: S → P | ||||||
Natural variant | VAR_058400 | 203 | enables membrane anchoring via glycosylphosphatidylinositol; disrupts transmembrane anchoring; dbSNP:rs1042206 | |||
Sequence: F → S | ||||||
Mutagenesis | 203 | Disrupts transmembrane anchoring. | ||||
Sequence: F → P | ||||||
Mutagenesis | 203 | Enables membrane anchoring via glycosylphosphatidylinositol. Disrupts transmembrane anchoring. | ||||
Sequence: F → T, Y, N, E, A, D, or K | ||||||
Mutagenesis | 203 | Enables only transmembrane anchoring. | ||||
Sequence: F → V, I, or L | ||||||
Mutagenesis | 208 | Decreases the association with either CD247 or FCER1G. | ||||
Sequence: Q → A | ||||||
Mutagenesis | 210 | Has no effect on complex association with CD247 or FCER1G. Decreases cell surface expression; when associated with A-211 and A-212. | ||||
Sequence: S → A | ||||||
Mutagenesis | 211 | Decreases the association with either CD247 or FCER1G. Decreases cell surface expression; when associated with A-210 and A-212. | ||||
Sequence: F → A | ||||||
Mutagenesis | 212 | Has no effect on complex formation with CD247 or FCER1G. Decreases cell surface expression; when associated with A-210 and A-211. | ||||
Sequence: C → A | ||||||
Mutagenesis | 219 | Decreases the association with either CD247 or FCER1G. Decreases cell surface expression. | ||||
Sequence: F → A | ||||||
Mutagenesis | 222 | Decreases the association with either CD247 or FCER1G. Strongly increases cell surface expression. | ||||
Sequence: D → A | ||||||
Mutagenesis | 222 | Strongly decreases complex formation with CD247 or FCER1G. | ||||
Sequence: D → E or K | ||||||
Mutagenesis | 222 | Has little effect on complex formation with CD247 or FCER1G. | ||||
Sequence: D → N | ||||||
Mutagenesis | 223 | Decreases the association with either CD247 or FCER1G. Decreases cell surface expression. | ||||
Sequence: T → A | ||||||
Mutagenesis | 226 | Decreases the association with either CD247 or FCER1G. Decreases cell surface expression; when associated with A-227 and A-228. | ||||
Sequence: Y → A | ||||||
Mutagenesis | 227 | Decreases the association with either CD247 or FCER1G. Decreases cell surface expression; when associated with A-226 and A-228. | ||||
Sequence: F → A | ||||||
Mutagenesis | 228 | Has little effect on complex formation with CD247 or FCER1G. Decreases cell surface expression; when associated with A-226 and A-227. | ||||
Sequence: S → A | ||||||
Mutagenesis | 235-237 | Loss of PKC-dependent phosphorylation. Abolishes pro-inflammatory cytokine production while enhancing cell degranulation. | ||||
Sequence: SST → AAA | ||||||
Mutagenesis | 249-254 | Impairs the interaction with S100A4. | ||||
Sequence: Missing |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 515 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for signal, chain, disulfide bond, glycosylation, modified residue.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Signal | 1-16 | |||||
Sequence: MWQLLLPTALLLLVSA | ||||||
Chain | PRO_0000015150 | 17-254 | Low affinity immunoglobulin gamma Fc region receptor III-A | |||
Sequence: GMRTEDLPKAVVFLEPQWYRVLEKDSVTLKCQGAYSPEDNSTQWFHNESLISSQASSYFIDAATVDDSGEYRCQTNLSTLSDPVQLEVHIGWLLLQAPRWVFKEEDPIHLRCHSWKNTALHKVTYLQNGKGRKYFHHNSDFYIPKATLKDSGSYFCRGLFGSKNVSSETVNITITQGLAVSTISSFFPPGYQVSFCLVMVLLFAVDTGLYFSVKTNIRSSTRDWKDHKFKWRKDPQDK | ||||||
Disulfide bond | 47↔89 | |||||
Sequence: CQGAYSPEDNSTQWFHNESLISSQASSYFIDAATVDDSGEYRC | ||||||
Glycosylation | 56 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 63 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 92 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Disulfide bond | 128↔172 | |||||
Sequence: CHSWKNTALHKVTYLQNGKGRKYFHHNSDFYIPKATLKDSGSYFC | ||||||
Glycosylation | 180 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 187 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Modified residue | 236 | Phosphoserine; by PKC | ||||
Sequence: S | ||||||
Modified residue | 237 | Phosphothreonine; by PKC | ||||
Sequence: T |
Post-translational modification
Glycosylated. Contains high mannose- and complex-type oligosaccharides. Glycosylation at Asn-180 is mandatory for high affinity binding to the Fc and for discrimination between fucosylated and afucosylated IgG glycoforms.
Undergoes rapid ectodomain shedding upon NK cell stimulation. The soluble form is produced by a proteolytic cleavage mediated by ADAM17. Repeated stimulation causes receptor shedding, a mechanism that allows for increased NK cell motility and detachment from opsonized target cells while avoiding activation-induced NK cell apoptosis.
Phosphorylated at RSSTR motif by PKC. The relevant physiological PKCs might be PRKCI, PRKCG, PRKCE, PRKCH and PRKCQ.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Expressed in natural killer cells (at protein level) (PubMed:2526846).
Expressed in a subset of circulating monocytes (at protein level) (PubMed:27670158).
Expressed in a subset of circulating monocytes (at protein level) (PubMed:27670158).
Induction
Up-regulated in a monocyte subset upon exposure to IL10, TGFB and MCSF.
Gene expression databases
Organism-specific databases
Interaction
Subunit
Forms a heterooligomeric complex with ITAM-containing signaling subunits, either a homodimer of CD247, a homodimer of FCER1G or a heterodimer of CD247 and FCER1G (PubMed:1825220, PubMed:2532305, PubMed:28652325).
Interacts (via transmembrane domain) with signaling subunits; this interaction is a prerequisite for receptor complex expression on the cell surface and intracellular signal transduction (PubMed:1825220, PubMed:2532305, PubMed:28652325).
Binds the Fc region of antigen-complexed IgG with a preference for IgG1 and IgG3 isotypes (PubMed:11711607, PubMed:21768335, PubMed:22023369, PubMed:8609432, PubMed:9242542).
Interacts with CD2; this interaction is involved in NK cell activation and cytotoxicity (PubMed:23006327).
Interacts with S100A4; this interaction inhibits PKC-dependent phosphorylation of FCGR3A (PubMed:23024279).
Interacts (via transmembrane domain) with signaling subunits; this interaction is a prerequisite for receptor complex expression on the cell surface and intracellular signal transduction (PubMed:1825220, PubMed:2532305, PubMed:28652325).
Binds the Fc region of antigen-complexed IgG with a preference for IgG1 and IgG3 isotypes (PubMed:11711607, PubMed:21768335, PubMed:22023369, PubMed:8609432, PubMed:9242542).
Interacts with CD2; this interaction is involved in NK cell activation and cytotoxicity (PubMed:23006327).
Interacts with S100A4; this interaction inhibits PKC-dependent phosphorylation of FCGR3A (PubMed:23024279).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | P08637 | KIR2DL4 Q99706 | 2 | EBI-2833956, EBI-10294579 | |
BINARY | P08637 | RNF40 O75150 | 2 | EBI-2833956, EBI-744408 |
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 24-105 | Ig-like C2-type 1 | ||||
Sequence: PKAVVFLEPQWYRVLEKDSVTLKCQGAYSPEDNSTQWFHNESLISSQASSYFIDAATVDDSGEYRCQTNLSTLSDPVQLEVH | ||||||
Domain | 107-189 | Ig-like C2-type 2 | ||||
Sequence: GWLLLQAPRWVFKEEDPIHLRCHSWKNTALHKVTYLQNGKGRKYFHHNSDFYIPKATLKDSGSYFCRGLFGSKNVSSETVNIT |
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Sequence processingThe displayed sequence is further processed into a mature form.
- Length254
- Mass (Da)29,089
- Last updated1990-08-01 v2
- ChecksumD38D178D32C67337
Computationally mapped potential isoform sequences
There are 6 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
H0Y755 | H0Y755_HUMAN | FCGR3A | 253 | ||
C9JC71 | C9JC71_HUMAN | FCGR3A | 135 | ||
A0A8V8TPL1 | A0A8V8TPL1_HUMAN | FCGR3A | 237 | ||
A0A8V8TQ03 | A0A8V8TQ03_HUMAN | FCGR3A | 269 | ||
A0A8V8TNB3 | A0A8V8TNB3_HUMAN | FCGR3A | 110 | ||
A0A8V8TNB8 | A0A8V8TNB8_HUMAN | FCGR3A | 262 |
Sequence caution
Features
Showing features for sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 106 | in Ref. 3; BAD96988/BAD97015 | ||||
Sequence: I → V | ||||||
Sequence conflict | 195 | in Ref. 5; AAH33678 | ||||
Sequence: A → S |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
X52645 EMBL· GenBank· DDBJ | CAA36870.1 EMBL· GenBank· DDBJ | mRNA | ||
AK223268 EMBL· GenBank· DDBJ | BAD96988.1 EMBL· GenBank· DDBJ | mRNA | Different initiation | |
AK223295 EMBL· GenBank· DDBJ | BAD97015.1 EMBL· GenBank· DDBJ | mRNA | Different initiation | |
AL590385 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
BC017865 EMBL· GenBank· DDBJ | AAH17865.1 EMBL· GenBank· DDBJ | mRNA | ||
BC033678 EMBL· GenBank· DDBJ | AAH33678.1 EMBL· GenBank· DDBJ | mRNA | ||
Z46222 EMBL· GenBank· DDBJ | CAA86295.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
S76824 EMBL· GenBank· DDBJ | AAB33925.2 EMBL· GenBank· DDBJ | mRNA | ||
M24853 EMBL· GenBank· DDBJ | AAA53506.1 EMBL· GenBank· DDBJ | mRNA |