P05109 · S10A8_HUMAN

  • Protein
    Protein S100-A8
  • Gene
    S100A8
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at protein level
  • Annotation score
    5/5

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.
(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.

TypeIDPosition(s)Description
Binding site17Zn2+ (UniProtKB | ChEBI)
Binding site27Zn2+ (UniProtKB | ChEBI)
Binding site33Ca2+ 1 (UniProtKB | ChEBI); low affinity
Binding site59Ca2+ 2 (UniProtKB | ChEBI); high affinity
Binding site61Ca2+ 2 (UniProtKB | ChEBI); high affinity
Binding site63Ca2+ 2 (UniProtKB | ChEBI); high affinity
Binding site70Ca2+ 2 (UniProtKB | ChEBI); high affinity
Binding site83Zn2+ (UniProtKB | ChEBI)
Binding site87Zn2+ (UniProtKB | ChEBI)

GO annotations

AspectTerm
Cellular Componentcalprotectin complex
Cellular Componentcollagen-containing extracellular matrix
Cellular Componentcytoskeleton
Cellular Componentcytosol
Cellular Componentextracellular exosome
Cellular Componentextracellular region
Cellular Componentextracellular space
Cellular Componentintermediate filament cytoskeleton
Cellular Componentnucleus
Cellular Componentplasma membrane
Cellular Componentsecretory granule lumen
Molecular Functionarachidonic acid binding
Molecular Functioncalcium ion binding
Molecular Functioncalcium-dependent protein binding
Molecular Functionmicrotubule binding
Molecular FunctionRAGE receptor binding
Molecular FunctionToll-like receptor 4 binding
Molecular Functionzinc ion binding
Biological Processactivation of cysteine-type endopeptidase activity involved in apoptotic process
Biological Processapoptotic process
Biological Processastrocyte development
Biological Processautocrine signaling
Biological Processautophagy
Biological Processchronic inflammatory response
Biological Processdefense response to bacterium
Biological Processdefense response to fungus
Biological Processinflammatory response
Biological Processinnate immune response
Biological Processleukocyte migration involved in inflammatory response
Biological Processneutrophil aggregation
Biological Processneutrophil chemotaxis
Biological Processpeptide secretion
Biological Processpeptidyl-cysteine S-nitrosylation
Biological Processpositive regulation of cell growth
Biological Processpositive regulation of inflammatory response
Biological Processpositive regulation of intrinsic apoptotic signaling pathway
Biological Processpositive regulation of NF-kappaB transcription factor activity
Biological Processpositive regulation of peptide secretion
Biological Processregulation of cytoskeleton organization
Biological Processregulation of toll-like receptor signaling pathway
Biological Processresponse to ethanol
Biological Processresponse to lipopolysaccharide
Biological Processresponse to zinc ion
Biological Processsequestering of zinc ion

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    Protein S100-A8
  • Alternative names
    • Calgranulin-A
    • Calprotectin L1L subunit
    • Cystic fibrosis antigen (CFAG)
    • Leukocyte L1 complex light chain
    • Migration inhibitory factor-related protein 8 (MRP-8; p8)

Gene names

    • Name
      S100A8
    • Synonyms
      CAGA, CFAG, MRP8

Organism names

  • Taxonomic identifier
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo

Accessions

  • Primary accession
    P05109
  • Secondary accessions
    • A8K5L3
    • D3DV37
    • Q5SY70
    • Q9UC84
    • Q9UC92

Proteomes

Organism-specific databases

Subcellular Location

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

Disease & Variants

Features

Showing features for mutagenesis.

TypeIDPosition(s)Description
Mutagenesis42Loss of antifungal activity.

Variants

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The viewer provides 110 variants from UniProt as well as other sources including ClinVar and dbSNP.

Go to variant viewer

Organism-specific databases

Miscellaneous

Chemistry

Genetic variation databases

PTM/Processing

Features

Showing features for chain, modified residue (large scale data), modified residue.

TypeIDPosition(s)SourceDescription
ChainPRO_00001439931-93UniProtProtein S100-A8
Modified residue (large scale data)11PRIDEPhosphoserine
Modified residue42UniProtS-nitrosocysteine

Keywords

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).

Binary interactions

TypeEntry 1Entry 2Number of experimentsIntact
BINARY P05109GAPDH P044066EBI-355281, EBI-354056
BINARY P05109S100A9 P067027EBI-355281, EBI-1055001
BINARY P05109TRPM4 Q8TD432EBI-355281, EBI-11723041

Protein-protein interaction databases

Miscellaneous

Family & Domains

Features

Showing features for domain.

TypeIDPosition(s)Description
Domain12-47EF-hand 1
Domain46-81EF-hand 2

Sequence similarities

Belongs to the S-100 family.

Keywords

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Length
    93
  • Mass (Da)
    10,835
  • Last updated
    1988-01-01 v1
  • Checksum
    78F589140B9CE166
MLTELEKALNSIIDVYHKYSLIKGNFHAVYRDDLKKLLETECPQYIRKKGADVWFKELDINTDGAVNFQEFLILVIKMGVAAHKKSHEESHKE

Features

Showing features for sequence conflict.

TypeIDPosition(s)Description
Sequence conflict80-93in Ref. 1; CAA68390

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
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

Genome annotation databases

Similar Proteins

Disclaimer

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