ID   S10AC_BOVIN             Reviewed;          92 AA.
AC   P79105; Q3T070; Q9TR16;
DT   01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT   23-JAN-2007, sequence version 3.
DT   02-SEP-2026, entry version 163.
DE   RecName: Full=Protein S100-A12;
DE   AltName: Full=Calcium-binding protein in amniotic fluid 1;
DE            Short=CAAF1;
DE   AltName: Full=Calgranulin-C;
DE            Short=CAGC;
DE   AltName: Full=Cornea-associated antigen;
DE            Short=CO-AG;
DE   AltName: Full=Extracellular newly identified RAGE-binding protein;
DE            Short=EN-RAGE;
DE   AltName: Full=RAGE-binding protein;
DE   AltName: Full=S100 calcium-binding protein A12;
GN   Name=S100A12; Synonyms=CAAF1;
OS   Bos taurus (Bovine).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC   Bovinae; Bos.
OX   NCBI_TaxID=9913;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Esophagus;
RX   PubMed=8718672; DOI=10.1242/jcs.109.4.805;
RA   Hitomi J., Yamaguchi K., Kikuchi Y., Kimura T., Maruyama K., Nagasaki K.;
RT   "A novel calcium-binding protein in amniotic fluid, CAAF1: its molecular
RT   cloning and tissue distribution.";
RL   J. Cell Sci. 109:805-815(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 1-51 AND 66-83, INTERACTION
RP   WITH AGER, AND TISSUE SPECIFICITY.
RC   TISSUE=Lung;
RX   PubMed=10399917; DOI=10.1016/s0092-8674(00)80801-6;
RA   Hofmann M.A., Drury S., Fu C., Qu W., Taguchi A., Lu Y., Avila C.,
RA   Kambham N., Bierhaus A., Nawroth P., Neurath M.F., Slattery T., Beach D.,
RA   McClary J., Nagashima M., Morser J., Stern D., Schmidt A.M.;
RT   "RAGE mediates a novel proinflammatory axis: a central cell surface
RT   receptor for S100/calgranulin polypeptides.";
RL   Cell 97:889-901(1999).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=Crossbred X Angus; TISSUE=Liver;
RG   NIH - Mammalian Gene Collection (MGC) project;
RL   Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   PROTEIN SEQUENCE OF 2-71.
RC   TISSUE=Corneal stroma;
RX   PubMed=8603881;
RA   Liu S.H., Gottsch J.D.;
RT   "Amino acid sequence of an immunogenic corneal stromal protein.";
RL   Invest. Ophthalmol. Vis. Sci. 37:944-948(1996).
CC   -!- FUNCTION: S100A12 is a calcium-, zinc- and copper-binding protein which
CC       plays a prominent role in the regulation of inflammatory processes and
CC       immune response. Its pro-inflammatory activity involves recruitment of
CC       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 receptor for advanced glycation
CC       endproducts (AGER). Binding to AGER activates the MAP-kinase and NF-
CC       kappa-B signaling pathways leading to production of pro-inflammatory
CC       cytokines and up-regulation of cell adhesion molecules ICAM1 and VCAM1.
CC       Acts as a monocyte and mast cell chemoattractant. Can stimulate mast
CC       cell degranulation and activation which generates chemokines, histamine
CC       and cytokines inducing further leukocyte recruitment to the sites of
CC       inflammation. Can inhibit the activity of matrix metalloproteinases;
CC       MMP2, MMP3 and MMP9 by chelating Zn(2+) from their active sites (By
CC       similarity). {ECO:0000250}.
CC   -!- SUBUNIT: Homodimer. Homooligomer (tetramer or hexamer) in the presence
CC       of calcium, zinc and copper ions. Interacts with AGER and both calcium
CC       and zinc are essential for the interaction (By similarity). Interacts
CC       with CACYBP in a calcium-dependent manner (By similarity).
CC       {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250}. Cytoplasm {ECO:0000250}.
CC       Cytoplasm, cytoskeleton {ECO:0000250}. Cell membrane {ECO:0000250};
CC       Peripheral membrane protein {ECO:0000250}. Note=Predominantly localized
CC       in the cytoplasm. Upon elevation of the intracellular calcium level,
CC       translocated from the cytoplasm to the cytoskeleton and the cell
CC       membrane. Upon neutrophil activation is secreted via a microtubule-
CC       mediated, alternative pathway (By similarity). {ECO:0000250}.
CC   -!- TISSUE SPECIFICITY: Up-regulated in stimulated inflammatory effector
CC       cells. {ECO:0000269|PubMed:10399917}.
CC   -!- DOMAIN: The hinge domain contributes significantly to its chemotactic
CC       properties. {ECO:0000250}.
CC   -!- SIMILARITY: Belongs to the S-100 family. {ECO:0000305}.
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DR   EMBL; D49548; BAA08496.1; -; mRNA.
DR   EMBL; AF011757; AAB65423.1; -; mRNA.
DR   EMBL; BC102542; AAI02543.1; -; mRNA.
DR   RefSeq; NP_777076.1; NM_174651.3.
DR   RefSeq; XP_005203669.1; XM_005203612.3.
DR   AlphaFoldDB; P79105; -.
DR   SMR; P79105; -.
DR   BioGRID; 159720; 6.
DR   FunCoup; P79105; 32.
DR   STRING; 9913.ENSBTAP00000034009; -.
DR   PaxDb; 9913-ENSBTAP00000034009; -.
DR   PeptideAtlas; P79105; -.
DR   Ensembl; ENSBTAT00085073334; ENSBTAP00085007394; ENSBTAG00085036151.
DR   Ensembl; ENSBTAT00090082495; ENSBTAP00090046801; ENSBTAG00090038719.
DR   GeneID; 282467; -.
DR   KEGG; bta:282467; -.
DR   CTD; 6283; -.
DR   VEuPathDB; HostDB:ENSBTAG00000012638; -.
DR   VGNC; VGNC:59189; S100A12.
DR   eggNOG; ENOG502SA01; Eukaryota.
DR   HOGENOM; CLU_138624_6_2_1; -.
DR   InParanoid; P79105; -.
DR   OMA; HEHLHEV; -.
DR   OrthoDB; 9909924at2759; -.
DR   Reactome; R-BTA-445989; TAK1-dependent IKK and NF-kappa-B activation.
DR   Reactome; R-BTA-6798695; Neutrophil degranulation.
DR   Reactome; R-BTA-879415; Advanced glycosylation endproduct receptor signaling.
DR   Reactome; R-BTA-933542; TRAF6 mediated NF-kB activation.
DR   Proteomes; UP000009136; Chromosome 3.
DR   Bgee; ENSBTAG00000012638; Expressed in anterior segment of eyeball and 102 other cell types or tissues.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
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:0050786; F:RAGE receptor binding; IBA:GO_Central.
DR   GO; GO:0061844; P:antimicrobial humoral immune response mediated by antimicrobial peptide; IBA:GO_Central.
DR   GO; GO:0043542; P:endothelial cell migration; IBA:GO_Central.
DR   GO; GO:0043303; P:mast cell degranulation; IDA:UniProtKB.
DR   GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IBA:GO_Central.
DR   CDD; cd05030; calgranulins; 1.
DR   FunFam; 1.10.238.10:FF:000044; Protein S100; 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:SF77; PROTEIN S100-A12; 1.
DR   PANTHER; PTHR11639; S100 CALCIUM-BINDING PROTEIN; 1.
DR   Pfam; PF00036; EF-hand_1; 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   1: Evidence at protein level;
KW   Calcium; Cell membrane; Copper; Cytoplasm; Cytoskeleton;
KW   Direct protein sequencing; Immunity; Inflammatory response;
KW   Innate immunity; Membrane; Metal-binding; Reference proteome; Repeat;
KW   Secreted; Zinc.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0000269|PubMed:8603881"
FT   CHAIN           2..92
FT                   /note="Protein S100-A12"
FT                   /id="PRO_0000144015"
FT   DOMAIN          13..48
FT                   /note="EF-hand 1"
FT                   /evidence="ECO:0000305"
FT   DOMAIN          49..84
FT                   /note="EF-hand 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   REGION          38..53
FT                   /note="Hinge domain"
FT                   /evidence="ECO:0000250"
FT   BINDING         16
FT                   /ligand="Cu cation"
FT                   /ligand_id="ChEBI:CHEBI:23378"
FT                   /evidence="ECO:0000250|UniProtKB:P80511"
FT   BINDING         16
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:P80511"
FT   BINDING         19
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="1"
FT                   /ligand_note="low affinity"
FT                   /evidence="ECO:0000250|UniProtKB:P80511"
FT   BINDING         24
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="1"
FT                   /ligand_note="low affinity"
FT                   /evidence="ECO:0000250|UniProtKB:P80511"
FT   BINDING         26
FT                   /ligand="Cu cation"
FT                   /ligand_id="ChEBI:CHEBI:23378"
FT                   /evidence="ECO:0000250|UniProtKB:P80511"
FT   BINDING         26
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:P80511"
FT   BINDING         27
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="1"
FT                   /ligand_note="low affinity"
FT                   /evidence="ECO:0000250|UniProtKB:P80511"
FT   BINDING         32
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="1"
FT                   /ligand_note="low affinity"
FT                   /evidence="ECO:0000250|UniProtKB:P80511"
FT   BINDING         62
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         64
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         66
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         86
FT                   /ligand="Cu cation"
FT                   /ligand_id="ChEBI:CHEBI:23378"
FT                   /evidence="ECO:0000250|UniProtKB:P80511"
FT   BINDING         86
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:P80511"
FT   BINDING         90
FT                   /ligand="Cu cation"
FT                   /ligand_id="ChEBI:CHEBI:23378"
FT                   /evidence="ECO:0000250|UniProtKB:P80511"
FT   BINDING         90
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:P80511"
FT   CONFLICT        31
FT                   /note="R -> Y (in Ref. 2; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        37
FT                   /note="I -> G (in Ref. 2; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        66
FT                   /note="D -> K (in Ref. 4; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        70
FT                   /note="S -> V (in Ref. 4; AA sequence)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   92 AA;  10685 MW;  060233882D7C901F CRC64;
     MTKLEDHLEG IINIFHQYSV RVGHFDTLNK RELKQLITKE LPKTLQNTKD QPTIDKIFQD
     LDADKDGAVS FEEFVVLVSR VLKTAHIDIH KE
//