S10A8_MOUSE
ID S10A8_MOUSE Reviewed; 89 AA.
AC P27005; P31724;
DT 01-AUG-1992, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 03-AUG-2022, entry version 166.
DE RecName: Full=Protein S100-A8 {ECO:0000305};
DE AltName: Full=Calgranulin-A;
DE AltName: Full=Chemotactic cytokine CP-10;
DE AltName: Full=Leukocyte L1 complex light chain;
DE AltName: Full=Migration inhibitory factor-related protein 8;
DE Short=MRP-8;
DE Short=p8;
DE AltName: Full=Pro-inflammatory S100 cytokine;
DE AltName: Full=S100 calcium-binding protein A8;
GN Name=S100a8 {ECO:0000312|MGI:MGI:88244}; Synonyms=Caga, Mrp8;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=BALB/cJ;
RX PubMed=1373330;
RA Lagasse E., Weissman I.L.;
RT "Mouse MRP8 and MRP14, two intracellular calcium-binding proteins
RT associated with the development of the myeloid lineage.";
RL Blood 79:1907-1915(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8454868;
RA Lackmann M., Rajasekariah P., Iismaa S.E., Jones G., Cornish C.J., Hu S.,
RA Simpson R.J., Moritz R.L., Geczy C.L.;
RT "Identification of a chemotactic domain of the pro-inflammatory S100
RT protein CP-10.";
RL J. Immunol. 150:2981-2991(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=129/SvJ; TISSUE=Liver;
RX PubMed=8611640; DOI=10.1016/0925-4439(95)00108-5;
RA Nacken W.K.F., Manitz M.P., Sorg C.;
RT "Molecular characterisation of the genomic locus of the mouse MRP8 gene.";
RL Biochim. Biophys. Acta 1315:1-5(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Mammary gland;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP PROTEIN SEQUENCE OF 2-77.
RC TISSUE=Spleen;
RX PubMed=1559987; DOI=10.1016/s0021-9258(18)42545-8;
RA Lackmann M., Cornish C.J., Simpson R.J., Moritz R.L., Geczy C.L.;
RT "Purification and structural analysis of a murine chemotactic cytokine (CP-
RT 10) with sequence homology to S100 proteins.";
RL J. Biol. Chem. 267:7499-7504(1992).
RN [6]
RP DISRUPTION PHENOTYPE.
RX PubMed=10438963;
RA Passey R.J., Williams E., Lichanska A.M., Wells C., Hu S., Geczy C.L.,
RA Little M.H., Hume D.A.;
RT "A null mutation in the inflammation-associated S100 protein S100A8 causes
RT early resorption of the mouse embryo.";
RL J. Immunol. 163:2209-2216(1999).
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, SUBUNIT, AND INTERACTION WITH TLR4 AND
RP LY96.
RX PubMed=17767165; DOI=10.1038/nm1638;
RA Vogl T., Tenbrock K., Ludwig S., Leukert N., Ehrhardt C.,
RA van Zoelen M.A.D., Nacken W., Foell D., van der Poll T., Sorg C., Roth J.;
RT "Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4,
RT promoting lethal, endotoxin-induced shock.";
RL Nat. Med. 13:1042-1049(2007).
RN [8]
RP FUNCTION, AND INTERACTION WITH AGER AND ATP2A2.
RX PubMed=18403730; DOI=10.1161/circresaha.107.167544;
RA Boyd J.H., Kan B., Roberts H., Wang Y., Walley K.R.;
RT "S100A8 and S100A9 mediate endotoxin-induced cardiomyocyte dysfunction via
RT the receptor for advanced glycation end products.";
RL Circ. Res. 102:1239-1246(2008).
RN [9]
RP S-NITROSYLATION AT CYS-42.
RX PubMed=18832721; DOI=10.4049/jimmunol.181.8.5627;
RA Lim S.Y., Raftery M., Cai H., Hsu K., Yan W.X., Hseih H.L., Watts R.N.,
RA Richardson D., Thomas S., Perry M., Geczy C.L.;
RT "S-nitrosylated S100A8: novel anti-inflammatory properties.";
RL J. Immunol. 181:5627-5636(2008).
RN [10]
RP REVIEW.
RX PubMed=20523765; DOI=10.2174/187152309789838975;
RA Hsu K., Champaiboon C., Guenther B.D., Sorenson B.S., Khammanivong A.,
RA Ross K.F., Geczy C.L., Herzberg M.C.;
RT "Anti-infective protective properties of S100 calgranulins.";
RL Antiinflamm. Antiallergy Agents Med. Chem. 8:290-305(2009).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Heart, Kidney, Liver, Lung, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [12]
RP REVIEW.
RX PubMed=20213444; DOI=10.1007/s00726-010-0528-0;
RA Goyette J., Geczy C.L.;
RT "Inflammation-associated S100 proteins: new mechanisms that regulate
RT function.";
RL Amino Acids 41:821-842(2011).
RN [13]
RP FUNCTION, FUNCTION (MICROBIAL INFECTION), AND ACTIVITY REGULATION.
RX PubMed=33388094; DOI=10.1016/j.chom.2020.12.016;
RA Guo Q., Zhao Y., Li J., Liu J., Yang X., Guo X., Kuang M., Xia H.,
RA Zhang Z., Cao L., Luo Y., Bao L., Wang X., Wei X., Deng W., Wang N.,
RA Chen L., Chen J., Zhu H., Gao R., Qin C., Wang X., You F.;
RT "Induction of alarmin S100A8/A9 mediates activation of aberrant neutrophils
RT in the pathogenesis of COVID-19.";
RL Cell Host Microbe 0:0-0(2020).
CC -!- FUNCTION: S100A8 is a calcium- and zinc-binding protein which plays a
CC prominent role in the regulation of inflammatory processes and immune
CC response. It can induce neutrophil chemotaxis and adhesion.
CC Predominantly found as calprotectin (S100A8/A9) which has a wide
CC plethora of intra- and extracellular functions. The intracellular
CC functions include: facilitating leukocyte arachidonic acid trafficking
CC and metabolism, modulation of the tubulin-dependent cytoskeleton during
CC migration of phagocytes and activation of the neutrophilic NADPH-
CC oxidase. Activates NADPH-oxidase by facilitating the enzyme complex
CC assembly at the cell membrane, transferring arachidonic acid, an
CC essential cofactor, to the enzyme complex and S100A8 contributes to the
CC enzyme assembly by directly binding to NCF2/P67PHOX. The extracellular
CC functions involve pro-inflammatory, antimicrobial, oxidant-scavenging
CC and apoptosis-inducing activities. Its pro-inflammatory activity
CC includes recruitment of leukocytes, promotion of cytokine and chemokine
CC production, and regulation of leukocyte adhesion and migration. Acts as
CC an alarmin or a danger associated molecular pattern (DAMP) molecule and
CC stimulates innate immune cells via binding to pattern recognition
CC receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced
CC glycation endproducts (AGER). Binding to TLR4 and AGER activates the
CC MAP-kinase and NF-kappa-B signaling pathways resulting in the
CC amplification of the pro-inflammatory cascade. Has antimicrobial
CC activity towards bacteria and fungi and exerts its antimicrobial
CC activity probably via chelation of Zn(2+) which is essential for
CC microbial growth. Can induce cell death via autophagy and apoptosis and
CC this occurs through the cross-talk of mitochondria and lysosomes via
CC reactive oxygen species (ROS) and the process involves BNIP3. Can
CC regulate neutrophil number and apoptosis by an anti-apoptotic effect;
CC regulates cell survival via ITGAM/ITGB and TLR4 and a signaling
CC mechanism involving MEK-ERK. Its role as an oxidant scavenger has a
CC protective role in preventing exaggerated tissue damage by scavenging
CC oxidants. The iNOS-S100A8/A9 transnitrosylase complex is proposed to
CC direct selective inflammatory stimulus-dependent S-nitrosylation of
CC multiple targets such as GAPDH, ANXA5, EZR, MSN and VIM by recognizing
CC a [IL]-x-C-x-x-[DE] motif; S100A8 seems to contribute to S-
CC nitrosylation site selectivity (By similarity).
CC {ECO:0000250|UniProtKB:P05109, ECO:0000269|PubMed:17767165,
CC ECO:0000269|PubMed:18403730, ECO:0000269|PubMed:33388094}.
CC -!- FUNCTION: (Microbial infection) Upon infection by murine coronavirus
CC (MHV-A59), induces expansion of aberrant immature neutrophils in a
CC TLR4-dependent manner. {ECO:0000269|PubMed:33388094}.
CC -!- ACTIVITY REGULATION: Calprotectin (S100A8/A9) activity on TLR4
CC signaling is inhibited by paquinimod. {ECO:0000269|PubMed:33388094}.
CC -!- SUBUNIT: Homodimer. Preferentially exists as a heterodimer or
CC heterotetramer with S100A9 known as calprotectin (S100A8/A9).
CC Calprotectin (S100A8/9) interacts with CEACAM3 and tubulin filaments in
CC a calcium-dependent manner. Heterotetrameric calprotectin (S100A8/A9)
CC interacts with ANXA6 and associates with tubulin filaments in activated
CC monocytes. S100A8 and calprotectin (S100A8/9) interact with
CC NCF2/P67PHOX, RAC1 and RAC2. Calprotectin (S100A8/9) interacts with
CC CYBA and CYBB (By similarity). S100A8 interacts with AGER, ATP2A2 and
CC with the heterodimeric complex formed by TLR4 and LY96. Calprotectin
CC (S100A8/9) interacts with NOS2 to form the iNOS-S100A8/A9
CC transnitrosylase complex (By similarity). {ECO:0000250,
CC ECO:0000250|UniProtKB:P05109, ECO:0000269|PubMed:17767165,
CC ECO:0000269|PubMed:18403730}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:17767165}. Cytoplasm
CC {ECO:0000250}. Cytoplasm, cytoskeleton {ECO:0000250}. Cell membrane
CC {ECO:0000250}; Peripheral membrane protein {ECO:0000250}.
CC Note=Predominantly localized in the cytoplasm. Upon elevation of the
CC intracellular calcium level, translocated from the cytoplasm to the
CC cytoskeleton and the cell membrane. Upon neutrophil activation or
CC endothelial adhesion of monocytes, is secreted via a microtubule-
CC mediated, alternative pathway.
CC -!- DISRUPTION PHENOTYPE: Death at an early embryonic stage due to embryo
CC resorption, starting about 8 days after fertilization.
CC {ECO:0000269|PubMed:10438963}.
CC -!- MISCELLANEOUS: Binds two calcium ions per molecule with an affinity
CC similar to that of the S-100 proteins. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the S-100 family. {ECO:0000305}.
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DR EMBL; M83218; AAB07229.1; -; mRNA.
DR EMBL; S57123; AAB25840.1; -; mRNA.
DR EMBL; X87966; CAA61204.1; -; Genomic_DNA.
DR EMBL; BC078629; AAH78629.1; -; mRNA.
DR CCDS; CCDS38507.1; -.
DR PIR; I56163; I56163.
DR RefSeq; NP_038678.1; NM_013650.2.
DR AlphaFoldDB; P27005; -.
DR SMR; P27005; -.
DR BioGRID; 203056; 1.
DR ComplexPortal; CPX-40; Calprotectin heterotetramer.
DR ComplexPortal; CPX-41; Calprotectin heterodimer.
DR ComplexPortal; CPX-47; S100A8 complex.
DR ComplexPortal; CPX-53; iNOS-S100A8/A9 complex.
DR IntAct; P27005; 1.
DR STRING; 10090.ENSMUSP00000064385; -.
DR iPTMnet; P27005; -.
DR PhosphoSitePlus; P27005; -.
DR PaxDb; P27005; -.
DR PeptideAtlas; P27005; -.
DR PRIDE; P27005; -.
DR ProteomicsDB; 256555; -.
DR Antibodypedia; 3463; 1325 antibodies from 44 providers.
DR DNASU; 20201; -.
DR Ensembl; ENSMUST00000069927; ENSMUSP00000064385; ENSMUSG00000056054.
DR GeneID; 20201; -.
DR KEGG; mmu:20201; -.
DR UCSC; uc008qdd.1; mouse.
DR CTD; 6279; -.
DR MGI; MGI:88244; S100a8.
DR VEuPathDB; HostDB:ENSMUSG00000056054; -.
DR eggNOG; ENOG502SA01; Eukaryota.
DR GeneTree; ENSGT00910000144329; -.
DR HOGENOM; CLU_138624_6_0_1; -.
DR InParanoid; P27005; -.
DR OMA; YHKYSLE; -.
DR OrthoDB; 1613717at2759; -.
DR PhylomeDB; P27005; -.
DR TreeFam; TF332727; -.
DR Reactome; R-MMU-5668599; RHO GTPases Activate NADPH Oxidases.
DR Reactome; R-MMU-5686938; Regulation of TLR by endogenous ligand.
DR Reactome; R-MMU-6798695; Neutrophil degranulation.
DR Reactome; R-MMU-6799990; Metal sequestration by antimicrobial proteins.
DR BioGRID-ORCS; 20201; 2 hits in 70 CRISPR screens.
DR PRO; PR:P27005; -.
DR Proteomes; UP000000589; Chromosome 3.
DR RNAct; P27005; protein.
DR Bgee; ENSMUSG00000056054; Expressed in granulocyte and 156 other tissues.
DR ExpressionAtlas; P27005; baseline and differential.
DR Genevisible; P27005; MM.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005615; C:extracellular space; ISO:MGI.
DR GO; GO:0045111; C:intermediate filament cytoskeleton; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016209; F:antioxidant activity; IEA:UniProtKB-KW.
DR GO; GO:0050544; F:arachidonic acid binding; IEA:InterPro.
DR GO; GO:0005509; F:calcium ion binding; IBA:GO_Central.
DR GO; GO:0048306; F:calcium-dependent protein binding; IBA:GO_Central.
DR GO; GO:0008017; F:microtubule binding; IEA:InterPro.
DR GO; GO:0050786; F:RAGE receptor binding; IEA:InterPro.
DR GO; GO:0035662; F:Toll-like receptor 4 binding; IEA:InterPro.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; ISS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0014002; P:astrocyte development; IGI:MGI.
DR GO; GO:0035425; P:autocrine signaling; ISO:MGI.
DR GO; GO:0006914; P:autophagy; ISS:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0002523; P:leukocyte migration involved in inflammatory response; ISS:UniProtKB.
DR GO; GO:0070488; P:neutrophil aggregation; ISS:UniProtKB.
DR GO; GO:0030593; P:neutrophil chemotaxis; ISS:UniProtKB.
DR GO; GO:0002790; P:peptide secretion; IDA:MGI.
DR GO; GO:0018119; P:peptidyl-cysteine S-nitrosylation; ISO:MGI.
DR GO; GO:0050729; P:positive regulation of inflammatory response; ISS:UniProtKB.
DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; ISS:UniProtKB.
DR GO; GO:0002793; P:positive regulation of peptide secretion; IDA:MGI.
DR GO; GO:0032496; P:response to lipopolysaccharide; IBA:GO_Central.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR InterPro; IPR002048; EF_hand_dom.
DR InterPro; IPR001751; S100/CaBP7/8-like_CS.
DR InterPro; IPR013787; S100_Ca-bd_sub.
DR InterPro; IPR028474; S100A8.
DR PANTHER; PTHR11639:SF5; PTHR11639:SF5; 1.
DR Pfam; PF01023; S_100; 1.
DR SMART; SM00054; EFh; 1.
DR SMART; SM01394; S_100; 1.
DR SUPFAM; SSF47473; SSF47473; 1.
DR PROSITE; PS00018; EF_HAND_1; 1.
DR PROSITE; PS50222; EF_HAND_2; 1.
DR PROSITE; PS00303; S100_CABP; 1.
PE 1: Evidence at protein level;
KW Antimicrobial; Antioxidant; Apoptosis; Autophagy; Calcium; Cell membrane;
KW Chemotaxis; Cytoplasm; Cytoskeleton; Direct protein sequencing; Immunity;
KW Inflammatory response; Innate immunity; Membrane; Metal-binding;
KW Reference proteome; Repeat; S-nitrosylation; Secreted; Zinc.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:1559987"
FT CHAIN 2..89
FT /note="Protein S100-A8"
FT /id="PRO_0000143994"
FT DOMAIN 13..48
FT /note="EF-hand 1"
FT /evidence="ECO:0000305"
FT DOMAIN 46..81
FT /note="EF-hand 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 17
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 27
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 33
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /ligand_note="low affinity"
FT /evidence="ECO:0000305"
FT BINDING 59
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /ligand_note="high affinity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 61
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /ligand_note="high affinity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 63
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /ligand_note="high affinity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 70
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /ligand_note="high affinity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 83
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT MOD_RES 42
FT /note="S-nitrosocysteine"
FT /evidence="ECO:0000269|PubMed:18832721"
FT CONFLICT 57
FT /note="E -> D (in Ref. 3; CAA61204)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 89 AA; 10295 MW; D2AFF46ACE867A28 CRC64;
MPSELEKALS NLIDVYHNYS NIQGNHHALY KNDFKKMVTT ECPQFVQNIN IENLFRELDI
NSDNAINFEE FLAMVIKVGV ASHKDSHKE
