P05109 · S10A8_HUMAN
- ProteinProtein S100-A8
- GeneS100A8
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
S100A8 is a calcium- and zinc-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response. It can induce neutrophil chemotaxis and adhesion. Predominantly found as calprotectin (S100A8/A9) which has a wide plethora of intra- and extracellular functions. The intracellular functions include: facilitating leukocyte arachidonic acid trafficking and metabolism, modulation of the tubulin-dependent cytoskeleton during migration of phagocytes and activation of the neutrophilic NADPH-oxidase. Participates also in regulatory T-cell differentiation together with CD69 (PubMed:26296369).
Activates NADPH-oxidase by facilitating the enzyme complex assembly at the cell membrane, transferring arachidonic acid, an essential cofactor, to the enzyme complex and S100A8 contributes to the enzyme assembly by directly binding to NCF2/P67PHOX. The extracellular functions involve pro-inflammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities. Its pro-inflammatory activity includes recruitment of leukocytes, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration. Acts as an alarmin or a danger associated molecular pattern (DAMP) molecule and stimulates innate immune cells via binding to pattern recognition receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (AGER). Binding to TLR4 and AGER activates the MAP-kinase and NF-kappa-B signaling pathways resulting in the amplification of the pro-inflammatory cascade. Has antimicrobial activity towards bacteria and fungi and exerts its antimicrobial activity probably via chelation of Zn2+ which is essential for microbial growth. Can induce cell death via autophagy and apoptosis and this occurs through the cross-talk of mitochondria and lysosomes via reactive oxygen species (ROS) and the process involves BNIP3. Can regulate neutrophil number and apoptosis by an anti-apoptotic effect; regulates cell survival via ITGAM/ITGB and TLR4 and a signaling mechanism involving MEK-ERK. Its role as an oxidant scavenger has a protective role in preventing exaggerated tissue damage by scavenging oxidants. Can act as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread. The iNOS-S100A8/A9 transnitrosylase complex directs selective inflammatory stimulus-dependent S-nitrosylation of GAPDH and probably multiple targets such as ANXA5, EZR, MSN and VIM by recognizing a [IL]-x-C-x-x-[DE] motif; S100A8 seems to contribute to S-nitrosylation site selectivity.
Activates NADPH-oxidase by facilitating the enzyme complex assembly at the cell membrane, transferring arachidonic acid, an essential cofactor, to the enzyme complex and S100A8 contributes to the enzyme assembly by directly binding to NCF2/P67PHOX. The extracellular functions involve pro-inflammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities. Its pro-inflammatory activity includes recruitment of leukocytes, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration. Acts as an alarmin or a danger associated molecular pattern (DAMP) molecule and stimulates innate immune cells via binding to pattern recognition receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (AGER). Binding to TLR4 and AGER activates the MAP-kinase and NF-kappa-B signaling pathways resulting in the amplification of the pro-inflammatory cascade. Has antimicrobial activity towards bacteria and fungi and exerts its antimicrobial activity probably via chelation of Zn2+ which is essential for microbial growth. Can induce cell death via autophagy and apoptosis and this occurs through the cross-talk of mitochondria and lysosomes via reactive oxygen species (ROS) and the process involves BNIP3. Can regulate neutrophil number and apoptosis by an anti-apoptotic effect; regulates cell survival via ITGAM/ITGB and TLR4 and a signaling mechanism involving MEK-ERK. Its role as an oxidant scavenger has a protective role in preventing exaggerated tissue damage by scavenging oxidants. Can act as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread. The iNOS-S100A8/A9 transnitrosylase complex directs selective inflammatory stimulus-dependent S-nitrosylation of GAPDH and probably multiple targets such as ANXA5, EZR, MSN and VIM by recognizing a [IL]-x-C-x-x-[DE] motif; S100A8 seems to contribute to S-nitrosylation site selectivity.
(Microbial infection) Upon infection by human coronavirus SARS-CoV-2, may induce expansion of aberrant immature neutrophils in a TLR4-dependent manner.
Miscellaneous
Binds two calcium ions per molecule with an affinity similar to that of the S100 proteins.
Activity regulation
Calprotectin (S100A8/A9) activity on TLR4 signaling is inhibited by paquinimod.
Features
Showing features for binding site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 17 | Zn2+ (UniProtKB | ChEBI) | ||||
Sequence: H | ||||||
Binding site | 27 | Zn2+ (UniProtKB | ChEBI) | ||||
Sequence: H | ||||||
Binding site | 33 | Ca2+ 1 (UniProtKB | ChEBI); low affinity | ||||
Sequence: D | ||||||
Binding site | 59 | Ca2+ 2 (UniProtKB | ChEBI); high affinity | ||||
Sequence: D | ||||||
Binding site | 61 | Ca2+ 2 (UniProtKB | ChEBI); high affinity | ||||
Sequence: N | ||||||
Binding site | 63 | Ca2+ 2 (UniProtKB | ChEBI); high affinity | ||||
Sequence: D | ||||||
Binding site | 70 | Ca2+ 2 (UniProtKB | ChEBI); high affinity | ||||
Sequence: E | ||||||
Binding site | 83 | Zn2+ (UniProtKB | ChEBI) | ||||
Sequence: H | ||||||
Binding site | 87 | Zn2+ (UniProtKB | ChEBI) | ||||
Sequence: H |
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameProtein S100-A8
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionP05109
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Cell membrane ; Peripheral membrane protein
Note: Predominantly localized in the cytoplasm. Upon elevation of the intracellular calcium level, translocated from the cytoplasm to the cytoskeleton and the cell membrane. Upon neutrophil activation or endothelial adhesion of monocytes, is secreted via a microtubule-mediated, alternative pathway.
Keywords
- Cellular component
Disease & Variants
Features
Showing features for mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 42 | Loss of antifungal activity. | ||||
Sequence: C → A |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 110 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 chain, modified residue (large scale data), modified residue.
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000143993 | 1-93 | UniProt | Protein S100-A8 | |||
Sequence: MLTELEKALNSIIDVYHKYSLIKGNFHAVYRDDLKKLLETECPQYIRKKGADVWFKELDINTDGAVNFQEFLILVIKMGVAAHKKSHEESHKE | |||||||
Modified residue (large scale data) | 11 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 42 | UniProt | S-nitrosocysteine | ||||
Sequence: C |
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Calprotectin (S100A8/9) is predominantly expressed in myeloid cells. Except for inflammatory conditions, the expression is restricted to a specific stage of myeloid differentiation since both proteins are expressed in circulating neutrophils and monocytes but are absent in normal tissue macrophages and lymphocytes. Under chronic inflammatory conditions, such as psoriasis and malignant disorders, also expressed in the epidermis. Found in high concentrations at local sites of inflammation or in the serum of patients with inflammatory diseases such as rheumatoid, cystic fibrosis, inflammatory bowel disease, Crohn's disease, giant cell arteritis, cystic fibrosis, Sjogren's syndrome, systemic lupus erythematosus, and progressive systemic sclerosis. Involved in the formation and deposition of amyloids in the aging prostate known as corpora amylacea inclusions. Strongly up-regulated in many tumors, including gastric, esophageal, colon, pancreatic, bladder, ovarian, thyroid, breast and skin cancers.
Induction
(Microbial infection) Expression is highly induced in CD14+ monocytes, neutrophils, and developing neutrophils of patients infected by SARS-COV-2.
Gene expression databases
Organism-specific databases
Interaction
Subunit
Homodimer. Preferentially exists as a heterodimer or heterotetramer with S100A9 known as calprotectin (S100A8/A9). S100A8 interacts with AGER, ATP2A2 and with the heterodimeric complex formed by TLR4 and LY96 (By similarity).
Interacts with GAPDH. Calprotectin (S100A8/9) interacts with CEACAM3 and tubulin filaments in a calcium-dependent manner. Heterotetrameric calprotectin (S100A8/A9) interacts with ANXA6 and associates with tubulin filaments in activated monocytes. S100A8 and calprotectin (S100A8/9) interact with NCF2/P67PHOX, RAC1 and RAC2. Calprotectin (S100A8/9) interacts with CYBA and CYBB. Calprotectin (S100A8/9) interacts with NOS2 to form the iNOS-S100A8/A9 transnitrosylase complex; induced by LDL(ox) (PubMed:25417112).
Calprotectin (S100A8/9) interacts with CD69 (PubMed:26296369).
Interacts with GAPDH. Calprotectin (S100A8/9) interacts with CEACAM3 and tubulin filaments in a calcium-dependent manner. Heterotetrameric calprotectin (S100A8/A9) interacts with ANXA6 and associates with tubulin filaments in activated monocytes. S100A8 and calprotectin (S100A8/9) interact with NCF2/P67PHOX, RAC1 and RAC2. Calprotectin (S100A8/9) interacts with CYBA and CYBB. Calprotectin (S100A8/9) interacts with NOS2 to form the iNOS-S100A8/A9 transnitrosylase complex; induced by LDL(ox) (PubMed:25417112).
Calprotectin (S100A8/9) interacts with CD69 (PubMed:26296369).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | P05109 | GAPDH P04406 | 6 | EBI-355281, EBI-354056 | |
BINARY | P05109 | S100A9 P06702 | 7 | EBI-355281, EBI-1055001 | |
BINARY | P05109 | TRPM4 Q8TD43 | 2 | EBI-355281, EBI-11723041 |
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 12-47 | EF-hand 1 | ||||
Sequence: IIDVYHKYSLIKGNFHAVYRDDLKKLLETECPQYIR | ||||||
Domain | 46-81 | EF-hand 2 | ||||
Sequence: IRKKGADVWFKELDINTDGAVNFQEFLILVIKMGVA |
Sequence similarities
Belongs to the S-100 family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length93
- Mass (Da)10,835
- Last updated1988-01-01 v1
- Checksum78F589140B9CE166
Features
Showing features for sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 80-93 | in Ref. 1; CAA68390 | ||||
Sequence: VAAHKKSHEESHKE → WQPTKKAMKKATKSS |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
Y00278 EMBL· GenBank· DDBJ | CAA68390.1 EMBL· GenBank· DDBJ | mRNA | ||
X06234 EMBL· GenBank· DDBJ | CAA29580.1 EMBL· GenBank· DDBJ | mRNA | ||
M21005 EMBL· GenBank· DDBJ | AAA36327.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AK291328 EMBL· GenBank· DDBJ | BAF84017.1 EMBL· GenBank· DDBJ | mRNA | ||
CR407674 EMBL· GenBank· DDBJ | CAG28602.1 EMBL· GenBank· DDBJ | mRNA | ||
BT007378 EMBL· GenBank· DDBJ | AAP36042.1 EMBL· GenBank· DDBJ | mRNA | ||
AL591704 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
CH471121 EMBL· GenBank· DDBJ | EAW53330.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471121 EMBL· GenBank· DDBJ | EAW53331.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC005928 EMBL· GenBank· DDBJ | AAH05928.1 EMBL· GenBank· DDBJ | mRNA |