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Protein

Protein S100-A8

Gene

S100A8

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

Functioni

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. 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 proinflammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities. Its proinflammatory 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 proinflammatory 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.12 Publications

Miscellaneous

Binds two calcium ions per molecule with an affinity similar to that of the S100 proteins.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi17ZincCurated1
Metal bindingi27ZincCurated1
Metal bindingi83ZincCurated1
Metal bindingi87ZincCurated1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Calcium bindingi20 – 331; low affinityAdd BLAST14
Calcium bindingi59 – 702; high affinityAdd BLAST12

GO - Molecular functioni

  • arachidonic acid binding Source: UniProtKB
  • calcium ion binding Source: UniProtKB
  • microtubule binding Source: UniProtKB
  • RAGE receptor binding Source: UniProtKB
  • Toll-like receptor 4 binding Source: UniProtKB
  • zinc ion binding Source: UniProtKB

GO - Biological processi

  • activation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
  • acute inflammatory response Source: Ensembl
  • antimicrobial humoral response Source: Reactome
  • apoptotic process Source: UniProtKB-KW
  • astrocyte development Source: Ensembl
  • autophagy Source: UniProtKB
  • chemokine production Source: UniProtKB
  • chronic inflammatory response Source: Ensembl
  • cytokine production Source: UniProtKB
  • defense response to bacterium Source: UniProtKB
  • defense response to fungus Source: UniProtKB
  • inflammatory response Source: ProtInc
  • innate immune response Source: UniProtKB-KW
  • leukocyte migration involved in inflammatory response Source: UniProtKB
  • neutrophil aggregation Source: UniProtKB
  • neutrophil chemotaxis Source: UniProtKB
  • neutrophil degranulation Source: Reactome
  • peptidyl-cysteine S-nitrosylation Source: UniProtKB
  • positive regulation of cell growth Source: UniProtKB
  • positive regulation of inflammatory response Source: UniProtKB
  • positive regulation of intrinsic apoptotic signaling pathway Source: UniProtKB
  • positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
  • positive regulation of peptide secretion Source: Ensembl
  • regulation of cytoskeleton organization Source: UniProtKB
  • response to ethanol Source: Ensembl
  • response to lipopolysaccharide Source: Ensembl
  • response to zinc ion Source: Ensembl
  • sequestering of zinc ion Source: UniProtKB
  • toll-like receptor signaling pathway Source: Reactome
  • wound healing Source: Ensembl

Keywordsi

Molecular functionAntimicrobial
Biological processApoptosis, Autophagy, Chemotaxis, Immunity, Inflammatory response, Innate immunity
LigandCalcium, Metal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-HSA-5686938 Regulation of TLR by endogenous ligand
R-HSA-6798695 Neutrophil degranulation
R-HSA-6799990 Metal sequestration by antimicrobial proteins

Names & Taxonomyi

Protein namesi
Recommended name:
Protein S100-A8
Alternative name(s):
Calgranulin-A
Calprotectin L1L subunit
Cystic fibrosis antigen
Short name:
CFAG
Leukocyte L1 complex light chain
Migration inhibitory factor-related protein 8
Short name:
MRP-8
Short name:
p8
S100 calcium-binding protein A8
Urinary stone protein band A
Gene namesi
Name:S100A8
Synonyms:CAGA, CFAG, MRP8
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

EuPathDBiHostDB:ENSG00000143546.9
HGNCiHGNC:10498 S100A8
MIMi123885 gene
neXtProtiNX_P05109

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

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Cytoskeleton, Membrane, Secreted

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi42C → A: Loss of antifungal activity. 1 Publication1

Organism-specific databases

DisGeNETi6279
OpenTargetsiENSG00000143546
PharmGKBiPA34910

Polymorphism and mutation databases

BioMutaiS100A8
DMDMi115442

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001439931 – 93Protein S100-A8Add BLAST93

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei42S-nitrosocysteine1 Publication1

Keywords - PTMi

S-nitrosylation

Proteomic databases

EPDiP05109
MaxQBiP05109
PaxDbiP05109
PeptideAtlasiP05109
PRIDEiP05109
ProteomicsDBi51795
TopDownProteomicsiP05109

2D gel databases

SWISS-2DPAGEiP05109

PTM databases

iPTMnetiP05109
PhosphoSitePlusiP05109

Expressioni

Tissue specificityi

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.2 Publications

Gene expression databases

BgeeiENSG00000143546
CleanExiHS_S100A8
GenevisibleiP05109 HS

Organism-specific databases

HPAiCAB002791
HPA024372

Interactioni

Subunit structurei

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).By similarity10 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • microtubule binding Source: UniProtKB
  • RAGE receptor binding Source: UniProtKB
  • Toll-like receptor 4 binding Source: UniProtKB

Protein-protein interaction databases

BioGridi112187, 59 interactors
ComplexPortaliCPX-37 Calprotectin heterotetramer
CPX-39 Calprotectin heterodimer
CPX-42 S100A8 complex
CPX-52 iNOS-S100A8/A9 complex
CORUMiP05109
DIPiDIP-1165N
IntActiP05109, 45 interactors
MINTiP05109
STRINGi9606.ENSP00000357721

Structurei

Secondary structure

193
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi4 – 20Combined sources17
Beta strandi22 – 25Combined sources4
Helixi31 – 41Combined sources11
Helixi44 – 47Combined sources4
Helixi51 – 58Combined sources8
Beta strandi63 – 66Combined sources4
Helixi68 – 86Combined sources19

3D structure databases

ProteinModelPortaliP05109
SMRiP05109
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP05109

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini12 – 47EF-hand 1PROSITE-ProRule annotationAdd BLAST36
Domaini46 – 81EF-hand 2PROSITE-ProRule annotationAdd BLAST36

Sequence similaritiesi

Belongs to the S-100 family.Curated

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiENOG410J2UM Eukaryota
ENOG4111CN5 LUCA
GeneTreeiENSGT00910000144329
HOVERGENiHBG001479
InParanoidiP05109
KOiK21127
OMAiIKGNYHA
OrthoDBiEOG091G13NB
PhylomeDBiP05109
TreeFamiTF332727

Family and domain databases

InterProiView protein in InterPro
IPR011992 EF-hand-dom_pair
IPR018247 EF_Hand_1_Ca_BS
IPR002048 EF_hand_dom
IPR001751 S100/CaBP-9k_CS
IPR013787 S100_Ca-bd_sub
IPR028474 S100A8
PANTHERiPTHR11639:SF5 PTHR11639:SF5, 1 hit
PfamiView protein in Pfam
PF01023 S_100, 1 hit
SMARTiView protein in SMART
SM01394 S_100, 1 hit
SUPFAMiSSF47473 SSF47473, 1 hit
PROSITEiView protein in PROSITE
PS00018 EF_HAND_1, 1 hit
PS50222 EF_HAND_2, 1 hit
PS00303 S100_CABP, 1 hit

Sequencei

Sequence statusi: Complete.

P05109-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MLTELEKALN SIIDVYHKYS LIKGNFHAVY RDDLKKLLET ECPQYIRKKG
60 70 80 90
ADVWFKELDI NTDGAVNFQE FLILVIKMGV AAHKKSHEES HKE
Length:93
Mass (Da):10,835
Last modified:January 1, 1988 - v1
Checksum:i78F589140B9CE166
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti80 – 93VAAHK…ESHKE → WQPTKKAMKKATKSS in CAA68390 (PubMed:3561500).CuratedAdd BLAST14

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Y00278 mRNA Translation: CAA68390.1
X06234 mRNA Translation: CAA29580.1
M21005 Genomic DNA Translation: AAA36327.1
AK291328 mRNA Translation: BAF84017.1
CR407674 mRNA Translation: CAG28602.1
BT007378 mRNA Translation: AAP36042.1
AL591704 Genomic DNA No translation available.
CH471121 Genomic DNA Translation: EAW53330.1
CH471121 Genomic DNA Translation: EAW53331.1
BC005928 mRNA Translation: AAH05928.1
CCDSiCCDS1038.1
PIRiA31848 BCHUCF
RefSeqiNP_001306126.1, NM_001319197.1
NP_001306127.1, NM_001319198.1
NP_001306130.1, NM_001319201.1
NP_002955.2, NM_002964.4
UniGeneiHs.416073

Genome annotation databases

EnsembliENST00000368732; ENSP00000357721; ENSG00000143546
ENST00000368733; ENSP00000357722; ENSG00000143546
GeneIDi6279
KEGGihsa:6279
UCSCiuc001fbs.3 human

Similar proteinsi

Entry informationi

Entry nameiS10A8_HUMAN
AccessioniPrimary (citable) accession number: P05109
Secondary accession number(s): A8K5L3
, D3DV37, Q5SY70, Q9UC84, Q9UC92, Q9UCJ0, Q9UCM6
Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 13, 1987
Last sequence update: January 1, 1988
Last modified: July 18, 2018
This is version 198 of the entry and version 1 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

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. SIMILARITY comments
    Index of protein domains and families

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