P80511 (S10AC_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Protein S100-A12

Alternative name(s):
CGRP
Calcium-binding protein in amniotic fluid 1
Short name=CAAF1
Calgranulin-C
Short name=CAGC
Extracellular newly identified RAGE-binding protein
Short name=EN-RAGE
Migration inhibitory factor-related protein 6
Short name=MRP-6
Short name=p6
Neutrophil S100 protein
S100 calcium-binding protein A12

Cleaved into the following chain:

1. Calcitermin

Gene names

Name:

S100A12

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	92 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	S100A12 is a calcium-, zinc- and copper-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response. Its proinflammatory activity involves 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 receptor for advanced glycation endproducts (AGER). Binding to AGER activates the MAP-kinase and NF-kappa-B signaling pathways leading to production of proinflammatory cytokines and up-regulation of cell adhesion molecules ICAM1 and VCAM1. Acts as a monocyte and mast cell chemoattractant. Can stimulate mast cell degranulation and activation which generates chemokines, histamine and cytokines inducing further leukocyte recruitment to the sites of inflammation. Can inhibit the activity of matrix metalloproteinases; MMP2, MMP3 and MMP9 by chelating Zn2+ from their active sites. Possesses filariacidal and filariastatic activity. Calcitermin possesses antifungal activity against C.albicans and is also active against E.coli and P.aeruginosa but not L.monocytogenes and S.aureus. Ref.9 Ref.12 Ref.13 Ref.16
Subunit structure	Homodimer. Homooligomer (tetramer or hexamer) in the presence of calcium, zinc and copper ions. Interacts with AGER and both calcium and zinc are essential for the interaction. Interacts with CACYBP in a calcium-dependent manner. Ref.10 Ref.16
Subcellular location	Secreted. Cytoplasm. Cytoplasm › cytoskeleton. 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 is secreted via a microtubule-mediated, alternative pathway. Ref.19
Tissue specificity	Predominantly expressed by neutrophils, monocytes and activated macrophages. Expressed by eosinophils and macrophages in asthmatic airways in regions where mast cells accumulate. Found in high concentrations in the serum of patients suffering from various inflammatory disorders, such as rheumatoid arthritis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and Kawasaki disease.
Domain	The hinge domain contributes significantly to its chemotactic properties. Ref.13
Sequence similarities	Belongs to the S-101 family. Contains 2 EF-hand domains.
Mass spectrometry	Molecular mass is 10444 Da from positions 2 - 92. Determined by ESI. Ref.9 Molecular mass is 1688.9 Da from positions 78 - 92. Determined by MALDI. Ref.9

Ontologies

Keywords
Biological process	Immunity Inflammatory response Innate immunity
Cellular component	Cell membrane Cytoplasm Cytoskeleton Membrane Secreted
Domain	Repeat
Ligand	Calcium Copper Metal-binding Zinc
Molecular function	Antibiotic Antimicrobial Fungicide
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	cytokine secretion Traceable author statement Ref.14. Source: UniProtKB defense response to bacterium Traceable author statement Ref.14. Source: UniProtKB defense response to fungus Inferred from direct assay Ref.9. Source: UniProtKB inflammatory response Traceable author statement Ref.5. Source: ProtInc innate immune response Traceable author statement Ref.14. Source: UniProtKB killing of cells of other organism Inferred from electronic annotation. Source: UniProtKB-KW mast cell activation Traceable author statement Ref.14. Source: UniProtKB monocyte chemotaxis Traceable author statement Ref.14. Source: UniProtKB neutrophil chemotaxis Traceable author statement Ref.14. Source: UniProtKB positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from direct assay PubMed 15033494. Source: UniProtKB positive regulation of MAP kinase activity Traceable author statement Ref.14. Source: UniProtKB positive regulation of NF-kappaB transcription factor activity Traceable author statement Ref.14. Source: UniProtKB positive regulation of inflammatory response Traceable author statement Ref.14. Source: UniProtKB xenobiotic metabolic process Inferred from direct assay Ref.9. Source: UniProtKB
Cellular_component	cytoskeleton Traceable author statement Ref.14. Source: UniProtKB cytosol Traceable author statement Ref.14. Source: UniProtKB extracellular region Traceable author statement Ref.14. Source: UniProtKB nucleus Inferred from direct assay PubMed 15033494. Source: UniProtKB plasma membrane Traceable author statement Ref.14. Source: UniProtKB
Molecular_function	RAGE receptor binding Inferred from direct assay Ref.16. Source: UniProtKB calcium ion binding Traceable author statement Ref.14. Source: UniProtKB copper ion binding Traceable author statement Ref.14. Source: UniProtKB zinc ion binding Traceable author statement Ref.9Ref.14. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.5 Ref.6 Ref.7 Ref.8

Chain

2 – 92

91

Protein S100-A12

PRO_0000045383

Peptide

78 – 92

15

Calcitermin Ref.9

PRO_0000004774

Regions

Domain

13 – 48

36

EF-hand 1

Domain

49 – 84

36

EF-hand 2

Calcium binding

19 – 32

14

1; low affinity By similarity

Calcium binding

62 – 73

12

2; high affinity By similarity

Region

38 – 53

16

Hinge domain

Sites

Metal binding

16

1

Zinc or copper

Metal binding

26

1

Zinc or copper

Metal binding

86

1

Zinc or copper

Metal binding

90

1

Zinc or copper

Experimental info

Sequence conflict

7

1

H → V AA sequence Ref.8

Sequence conflict

12 – 13

2

VN → YS AA sequence Ref.8

Sequence conflict

16

1

H → F AA sequence Ref.8

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

92

Helix Strand Turn

Details...

Helix

3 – 19

17

Beta strand

21 – 24

4

Beta strand

27 – 29

3

Helix

30 – 40

11

Helix

42 – 47

6

Helix

51 – 58

8

Beta strand

61 – 64

4

Beta strand

67 – 70

4

Helix

71 – 89

19

Sequences

	Sequence		Length	Mass (Da)
	P80511 [UniParc]. Last modified January 23, 2007. Version 2. Checksum: 52AF75A31BDC222A	FASTA	92	10,575
	10 20 30 40 50 60 MTKLEEHLEG IVNIFHQYSV RKGHFDTLSK GELKQLLTKE LANTIKNIKD KAVIDEIFQG 70 80 90 LDANQDEQVD FQEFISLVAI ALKAAHYHTH KE

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human CAAF1 gene -- molecular cloning, gene structure, and chromosome mapping." Yamamura T., Hitomi J., Nagasaki K., Suzuki M., Takahashi E., Saito S., Tsukada T., Yamaguchi K. Biochem. Biophys. Res. Commun. 221:356-360(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
[2]	"Characterization of the human S100A12 (calgranulin C, p6, CAAF1, CGRP) gene, a new member of the S100 gene cluster on chromosome 1q21." Wicki R., Marenholz I., Mischke D., Schaefer B.W., Heizmann C.W. Cell Calcium 20:459-464(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
[3]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Blood.
[5]	"Host-parasite interaction in human onchocerciasis: identification and sequence analysis of a novel human calgranulin." Marti T., Erttmann K.D., Gallin M.Y. Biochem. Biophys. Res. Commun. 221:454-458(1996) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-92.
[6]	"Amino acid sequence determination of human S100A12 (P6, calgranulin C, CGRP, CAAF1) by tandem mass spectrometry." Ilg E.C., Troxler H., Buergisser D.M., Kuster T., Markert M., Guignard F., Hunziker P., Birchler N., Heizmann C.W. Biochem. Biophys. Res. Commun. 225:146-150(1996) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-92. Tissue: Neutrophil.
[7]	"Identification and characterization of a novel human neutrophil protein related to the S100 family." Guignard F., Mauel J., Markert M. Biochem. J. 309:395-401(1995) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-21.
[8]	"Identification, isolation, and partial characterization of a 7.5-kDa surfactant-associated protein." Singh G., Katyal S.L., Brown W.E., Kennedy A.L., Wong-Chong M.-L., Gottron S.A. Exp. Lung Res. 17:559-567(1991) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-16.
[9]	"Calcitermin, a novel antimicrobial peptide isolated from human airway secretions." Cole A.M., Kim Y.-H., Tahk S., Hong T., Weis P., Waring A.J., Ganz T. FEBS Lett. 504:5-10(2001) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 78-92, FUNCTION AS AN ANTIMICROBIAL PROTEIN, MASS SPECTROMETRY. Tissue: Nasal mucus.
[10]	"CacyBP/SIP, a calcyclin and Siah-1-interacting protein, binds EF-hand proteins of the S100 family." Filipek A., Jastrzebska B., Nowotny M., Kuznicki J. J. Biol. Chem. 277:28848-28852(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CACYBP.
[11]	"Multiple structural states of S100A12: A key to its functional diversity." Moroz O.V., Dodson G.G., Wilson K.S., Lukanidin E., Bronstein I.B. Microsc. Res. Tech. 60:581-592(2003) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[12]	"S100A12 provokes mast cell activation: a potential amplification pathway in asthma and innate immunity." Yang Z., Yan W.X., Cai H., Tedla N., Armishaw C., Di Girolamo N., Wang H.W., Hampartzoumian T., Simpson J.L., Gibson P.G., Hunt J., Hart P., Hughes J.M., Perry M.A., Alewood P.F., Geczy C.L. J. Allergy Clin. Immunol. 119:106-114(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[13]	"Mast cell and monocyte recruitment by S100A12 and its hinge domain." Yan W.X., Armishaw C., Goyette J., Yang Z., Cai H., Alewood P., Geczy C.L. J. Biol. Chem. 283:13035-13043(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, DOMAIN HINGE.
[14]	"Human S100A12: a novel key player in inflammation?" Pietzsch J., Hoppmann S. Amino Acids 36:381-389(2009) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[15]	"Anti-infective protective properties of S100 calgranulins." Hsu K., Champaiboon C., Guenther B.D., Sorenson B.S., Khammanivong A., Ross K.F., Geczy C.L., Herzberg M.C. Antiinflamm. Antiallergy Agents Med. Chem. 8:290-305(2009) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[16]	"Both Ca2+ and Zn2+ are essential for S100A12 protein oligomerization and function." Moroz O.V., Burkitt W., Wittkowski H., He W., Ianoul A., Novitskaya V., Xie J., Polyakova O., Lednev I.K., Shekhtman A., Derrick P.J., Bjoerk P., Foell D., Bronstein I.B. BMC Biochem. 10:11-11(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBUNIT, INTERACTION WITH AGER.
[17]	"S100 Calgranulins in inflammatory arthritis." Perera C., McNeil H.P., Geczy C.L. Immunol. Cell Biol. 88:41-49(2010) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[18]	"Inflammation-associated S100 proteins: new mechanisms that regulate function." Goyette J., Geczy C.L. Amino Acids 41:821-842(2011) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[19]	"The role of S100A12 as a systemic marker of inflammation." Meijer B., Gearry R.B., Day A.S. Int. J. Inflamm. 2012:907078-907078(2012) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW, SUBCELLULAR LOCATION.
[20]	"The three-dimensional structure of human S100A12." Moroz O.V., Antson A.A., Murshudov G.N., Maitland N.J., Dodson G.G., Wilson K.S., Skibshoj I., Lukanidin E.M., Bronstein I.B. Acta Crystallogr. D 57:20-29(2001) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS).
[21]	"Structure of the human S100A12-copper complex: implications for host-parasite defence." Moroz O.V., Antson A.A., Grist S.J., Maitland N.J., Dodson G.G., Wilson K.S., Lukanidin E., Bronstein I.B. Acta Crystallogr. D 59:859-867(2003) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.19 ANGSTROMS), COPPER-BINDING.
[22]	"The crystal structures of human S100A12 in apo form and in complex with zinc: new insights into S100A12 oligomerisation." Moroz O.V., Blagova E.V., Wilkinson A.J., Wilson K.S., Bronstein I.B. J. Mol. Biol. 391:536-551(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.88 ANGSTROMS) OF 2-92, ZINC-BINDING.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

D49549 mRNA. Translation: BAA08497.1.
D83657 Genomic DNA. Translation: BAA12030.1.
D83664 mRNA. Translation: BAA12036.1.
X97859 mRNA. Translation: CAA66453.1.
X98289, X98290 Genomic DNA. Translation: CAB94792.1.
AL591704 Genomic DNA. Translation: CAI19495.1.
BC070294 mRNA. Translation: AAH70294.1.

IPI

IPI00218131.

PIR

A61522.
JC4712.

RefSeq

NP_005612.1. NM_005621.1.

UniGene

Hs.19413.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1E8A	X-ray	1.95	A/B	2-92	[»]
1GQM	X-ray	2.70	A/B/C/D/E/F/G/H/I/J/K/L	2-92	[»]
1ODB	X-ray	2.19	A/B/C/D/E/F	2-92	[»]
2WC8	X-ray	1.88	A/B/C/D	2-92	[»]
2WCB	X-ray	1.73	A/B	2-92	[»]
2WCE	X-ray	1.77	A/B	2-92	[»]
2WCF	X-ray	2.78	A/B/C/D/E/F	2-92	[»]

ProteinModelPortal

P80511.

ModBase

Search...

Protein-protein interaction databases

IntAct

P80511. 1 interaction.

STRING

9606.ENSP00000357726.

PTM databases

PhosphoSite

P80511.

Polymorphism databases

DMDM

2507565.

Proteomic databases

PaxDb

P80511.

PRIDE

P80511.

Protocols and materials databases

DNASU

6283.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000368737; ENSP00000357726; ENSG00000163221.

GeneID

6283.

KEGG

hsa:6283.

UCSC

uc001fbr.1. human.

Organism-specific databases

CTD

6283.

GeneCards

GC01M153346.

HGNC

HGNC:10489. S100A12.

HPA

CAB025872.
HPA002881.

MIM

603112. gene.

neXtProt

NX_P80511.

PharmGKB

PA34901.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG87949.

HOGENOM

HOG000246968.

HOVERGEN

HBG001479.

InParanoid

P80511.

OMA

HYHTHKE.

OrthoDB

EOG4FFD3C.

PhylomeDB

P80511.

Enzyme and pathway databases

Reactome

REACT_6900. Immune System.

Gene expression databases

Bgee

P80511.

CleanEx

HS_S100A12.

Genevestigator

P80511.

GermOnline

ENSG00000163221. Homo sapiens.

Family and domain databases

Gene3D

1.10.238.10. 1 hit.

InterPro

IPR011992. EF-hand-like_dom.
IPR002048. EF_hand_dom.
IPR001751. S100/CaBP-9k_CS.
IPR013787. S100_Ca-bd_sub.
[Graphical view]

Pfam

PF01023. S_100. 1 hit.
[Graphical view]

PROSITE

PS00018. EF_HAND_1. False negative.
PS50222. EF_HAND_2. 1 hit.
PS00303. S100_CABP. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

DrugBank

DB01025. Amlexanox.

EvolutionaryTrace

P80511.

GenomeRNAi

6283.

NextBio

24389.

SOURCE

Search...

Entry information

Entry name

S10AC_HUMAN

Accession

Primary (citable) accession number: P80511
Secondary accession number(s): P83219, Q5SY66, Q7M4R1

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	January 23, 2007
Last modified:	May 1, 2013
This is version 131 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.