ID S10A9_RABIT Reviewed; 132 AA.
AC P50117; G1SVJ6; G8XUT3;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 31-OCT-2012, sequence version 3.
DT 27-MAR-2024, entry version 138.
DE RecName: Full=Protein S100-A9;
DE AltName: Full=Calgranulin-B;
DE AltName: Full=Migration inhibitory factor-related protein 14;
DE Short=MRP-14;
DE Short=p14;
DE AltName: Full=S100 calcium-binding protein A9;
GN Name=S100A9; Synonyms=MRP14;
OS Oryctolagus cuniculus (Rabbit).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae; Oryctolagus.
OX NCBI_TaxID=9986;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Liu Y., Chu T.;
RT "Cloning, characterization, and functional identification of a new
RT calgranulin gene from Oryctolagus cuniculus.";
RL Submitted (DEC-2008) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Thorbecke;
RG The Genome Sequencing Platform;
RA Di Palma F., Heiman D., Young S., Gnerre S., Johnson J., Lander E.S.,
RA Lindblad-Toh K.;
RT "Genome Sequence of Oryctolagus cuniculus (European rabbit).";
RL Submitted (AUG-2009) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 15-132.
RC STRAIN=New Zealand white; TISSUE=Neutrophil;
RX PubMed=8702688; DOI=10.1074/jbc.271.33.19802;
RA Yang Z., de Veer M.J., Gardiner E.E., Devenish R.J., Handley C.J.,
RA Underwood J.R., Robinson H.C.;
RT "Rabbit polymorphonuclear neutrophils form 35S-labeled S-sulfo-calgranulin
RT C when incubated with inorganic [35S]sulfate.";
RL J. Biol. Chem. 271:19802-19809(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 59-96.
RC STRAIN=New Zealand white;
RX PubMed=8148323; DOI=10.1093/intimm/6.1.149;
RA Mori S., Goto K., Goto F., Mutakami K., Ohkawara S., Yoshinaga M.;
RT "Dynamic changes in mRNA expression of neutrophils during the course of
RT acute inflammation in rabbits.";
RL Int. Immunol. 6:149-156(1994).
CC -!- FUNCTION: S100A9 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, adhesion, can increase
CC the bactericidal activity of neutrophils by promoting phagocytosis via
CC activation of SYK, PI3K/AKT, and ERK1/2 and can induce degranulation of
CC neutrophils by a MAPK-dependent mechanism. Predominantly found as
CC calprotectin (S100A8/A9) which has a wide plethora of intra- and
CC extracellular functions. The intracellular functions include:
CC facilitating leukocyte arachidonic acid trafficking and metabolism,
CC modulation of the tubulin-dependent cytoskeleton during migration of
CC phagocytes and activation of the neutrophilic NADPH-oxidase. Activates
CC NADPH-oxidase by facilitating the enzyme complex assembly at the cell
CC membrane, transferring arachidonic acid, an essential cofactor, to the
CC enzyme complex and S100A8 contributes to the enzyme assembly by
CC directly binding to NCF2/P67PHOX. The extracellular functions involve
CC pro-inflammatory, antimicrobial, oxidant-scavenging and apoptosis-
CC inducing activities. Its pro-inflammatory activity includes recruitment
CC of leukocytes, promotion of cytokine and chemokine production, and
CC regulation of leukocyte adhesion and migration. Acts as an alarmin or a
CC danger associated molecular pattern (DAMP) molecule and stimulates
CC innate immune cells via binding to pattern recognition receptors such
CC as Toll-like receptor 4 (TLR4) and receptor for advanced glycation
CC endproducts (AGER). Binding to TLR4 and AGER activates the MAP-kinase
CC and NF-kappa-B signaling pathways resulting in the amplification of the
CC pro-inflammatory cascade. Has antimicrobial activity towards bacteria
CC and fungi and exerts its antimicrobial activity probably via chelation
CC of Zn(2+) which is essential for microbial growth. Can induce cell
CC death via autophagy and apoptosis and this occurs through the cross-
CC talk of mitochondria and lysosomes via reactive oxygen species (ROS)
CC and the process involves BNIP3. Can regulate neutrophil number and
CC apoptosis by an anti-apoptotic effect; regulates cell survival via
CC ITGAM/ITGB and TLR4 and a signaling mechanism involving MEK-ERK. Its
CC role as an oxidant scavenger has a protective role in preventing
CC exaggerated tissue damage by scavenging oxidants. The iNOS-S100A8/A9
CC transnitrosylase complex is proposed to direct selective inflammatory
CC stimulus-dependent S-nitrosylation of multiple targets such as GAPDH,
CC NXA5, EZR, MSN and VIM by recognizing a [IL]-x-C-x-x-[DE] motif.
CC {ECO:0000250|UniProtKB:P06702}.
CC -!- SUBUNIT: Homodimer. Preferentially exists as a heterodimer or
CC heterotetramer with S100A8 known as calprotectin (S100A8/A9) (By
CC similarity). S100A9 interacts with ATP2A2 (By similarity). S100A9
CC interacts with AGER, and with the heterodimeric complex formed by TLR4
CC and LY96 in the presence of calcium and/or zinc ions. S100A9 binds
CC quinoline-3-carboxamides in the presence of calcium and/or zinc ions.
CC S100A9 interacts with amyloid-beta protein 40. Calprotectin (S100A8/9)
CC interacts with CEACAM3 and tubulin filaments in a calcium-dependent
CC manner. Heterotetrameric calprotectin (S100A8/A9) interacts with ANXA6
CC and associates with tubulin filaments in activated monocytes.
CC Calprotectin (S100A8/9) interacts with NCF2/P67PHOX, RAC1, RAC2, CYBA
CC and CYBB. Calprotectin (S100A8/9) interacts with NOS2 to form the iNOS-
CC S100A8/A9 transnitrosylase complex; induced by LDL(ox) (By similarity).
CC {ECO:0000250|UniProtKB:P06702, ECO:0000250|UniProtKB:P31725}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:P06702}.
CC Cytoplasm {ECO:0000250|UniProtKB:P06702}. Cytoplasm, cytoskeleton
CC {ECO:0000250|UniProtKB:P06702}. Cell membrane
CC {ECO:0000250|UniProtKB:P06702}; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:P06702}. Note=Predominantly localized in the
CC cytoplasm. Upon elevation of the intracellular calcium level,
CC translocated from the cytoplasm to the cytoskeleton and the cell
CC membrane. Upon neutrophil activation or endothelial adhesion of
CC monocytes, is secreted via a microtubule-mediated, alternative pathway.
CC {ECO:0000250|UniProtKB:P06702}.
CC -!- PTM: Phosphorylated. Phosphorylation inhibits activation of tubulin
CC polymerization. {ECO:0000250|UniProtKB:P06702}.
CC -!- PTM: Methylation at His-107 by METTL9 reduces zinc-binding without
CC affecting heterodimerization with S100A8.
CC {ECO:0000250|UniProtKB:P31725}.
CC -!- SIMILARITY: Belongs to the S-100 family. {ECO:0000305}.
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DR EMBL; FJ571519; ACY30467.1; -; mRNA.
DR EMBL; AAGW02000522; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AF091849; AAC61771.1; -; mRNA.
DR EMBL; D17404; BAA04227.1; -; mRNA.
DR PIR; I46861; I46861.
DR RefSeq; NP_001243402.1; NM_001256473.1.
DR RefSeq; XP_017200972.1; XM_017345483.1.
DR AlphaFoldDB; P50117; -.
DR SMR; P50117; -.
DR STRING; 9986.ENSOCUP00000007456; -.
DR PaxDb; 9986-ENSOCUP00000007456; -.
DR Ensembl; ENSOCUT00000008626.4; ENSOCUP00000007456.4; ENSOCUG00000008632.4.
DR GeneID; 100008704; -.
DR KEGG; ocu:100008704; -.
DR CTD; 6280; -.
DR eggNOG; ENOG502SA01; Eukaryota.
DR GeneTree; ENSGT00940000161606; -.
DR InParanoid; P50117; -.
DR OrthoDB; 4607525at2759; -.
DR TreeFam; TF332727; -.
DR Proteomes; UP000001811; Chromosome 13.
DR Bgee; ENSOCUG00000008632; Expressed in blood and 18 other cell types or tissues.
DR ExpressionAtlas; P50117; baseline.
DR GO; GO:1990660; C:calprotectin complex; IEA:Ensembl.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005615; C:extracellular space; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:1990662; C:S100A9 complex; IEA:Ensembl.
DR GO; GO:0016209; F:antioxidant activity; IEA:UniProtKB-KW.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; ISS:UniProtKB.
DR GO; GO:0061844; P:antimicrobial humoral immune response mediated by antimicrobial peptide; IEA:Ensembl.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
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:0035821; P:modulation of process of another organism; IEA:Ensembl.
DR GO; GO:0070488; P:neutrophil aggregation; ISS:UniProtKB.
DR GO; GO:0030593; P:neutrophil chemotaxis; ISS:UniProtKB.
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 CDD; cd05030; calgranulins; 1.
DR Gene3D; 1.10.238.10; EF-hand; 1.
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 PANTHER; PTHR11639:SF79; PROTEIN S100-A9; 1.
DR PANTHER; PTHR11639; S100 CALCIUM-BINDING PROTEIN; 1.
DR Pfam; PF01023; S_100; 1.
DR SMART; SM00054; EFh; 1.
DR SMART; SM01394; S_100; 1.
DR SUPFAM; SSF47473; EF-hand; 1.
DR PROSITE; PS00018; EF_HAND_1; 1.
DR PROSITE; PS50222; EF_HAND_2; 1.
DR PROSITE; PS00303; S100_CABP; 1.
PE 2: Evidence at transcript level;
KW Antimicrobial; Antioxidant; Apoptosis; Autophagy; Calcium; Cell membrane;
KW Chemotaxis; Cytoplasm; Cytoskeleton; Immunity; Inflammatory response;
KW Innate immunity; Membrane; Metal-binding; Methylation; Phosphoprotein;
KW Reference proteome; Repeat; S-nitrosylation; Secreted; Zinc.
FT CHAIN 1..132
FT /note="Protein S100-A9"
FT /id="PRO_0000144000"
FT DOMAIN 26..61
FT /note="EF-hand 1"
FT /evidence="ECO:0000305"
FT DOMAIN 54..89
FT /note="EF-hand 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT REPEAT 117..124
FT /note="1"
FT REPEAT 125..132
FT /note="2"
FT REGION 92..132
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 117..132
FT /note="2 X 8 AA tandem repeats of G-H-G-H-G-H-S-H"
FT COMPBIAS 92..107
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 20
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:P06702"
FT BINDING 23
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /ligand_note="low affinity"
FT /evidence="ECO:0000250|UniProtKB:P06702"
FT BINDING 30
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:P06702"
FT BINDING 36
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /ligand_note="low affinity"
FT /evidence="ECO:0000250|UniProtKB:P06702"
FT BINDING 67
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 69
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 71
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 73
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 78
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 91
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:P06702"
FT BINDING 95
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:P06702"
FT MOD_RES 3
FT /note="S-nitrosocysteine"
FT /evidence="ECO:0000250|UniProtKB:P06702"
FT MOD_RES 107
FT /note="Pros-methylhistidine"
FT /evidence="ECO:0000250|UniProtKB:P50116"
FT CONFLICT 18
FT /note="V -> I (in Ref. 3; AAC61771)"
FT /evidence="ECO:0000305"
FT CONFLICT 114
FT /note="G -> S (in Ref. 3; AAC61771)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 132 AA; 14787 MW; B84E662B7310F4E8 CRC64;
MSCGMSQLER SIDTIINVFH QYSVRVGPRD SLSQKEFKQL VQKELHNFLK KEARDEKAIN
DIMEDLDTNQ DKQLSFEEFV ILMARLVHAS HEEMHKNAPH DHEGHSHGPG LGGGGPGHGH
GHSHGHGHGH SH
//
