P50115 (S10A8_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Protein S100-A8

Alternative name(s):
Calgranulin-A
Migration inhibitory factor-related protein 8
Short name=MRP-8
Short name=p8
S100 calcium-binding protein A8

Gene names

Name:	S100a8
Synonyms:	Mrp8

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	89 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	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, transfering 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 proinfammatory, 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. Ref.3
Subunit structure	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. 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 By similarity.
Subcellular location	Secreted By similarity. Cytoplasm. Cytoplasm › cytoskeleton By similarity. Cell membrane; Peripheral membrane protein By similarity. 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 or endothelial adhesion of monocytes, is secreted via a microtubule-mediated, alternative pathway By similarity. Ref.3
Miscellaneous	Binds two calcium ions per molecule with an affinity similar to that of the S100 proteins By similarity.
Sequence similarities	Belongs to the S-100 family. Contains 2 EF-hand domains.
Mass spectrometry	Molecular mass is 10149±2 Da from positions 2 - 89. Determined by ESI. Ref.2

Ontologies

Keywords
Biological process	Apoptosis Autophagy Chemotaxis Immunity Inflammatory response Innate immunity
Cellular component	Cell membrane Cytoplasm Cytoskeleton Membrane Secreted
Domain	Repeat
Ligand	Calcium Metal-binding Zinc
Molecular function	Antimicrobial Antioxidant
PTM	Acetylation S-nitrosylation
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	activation of cysteine-type endopeptidase activity involved in apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB acute inflammatory response Inferred from expression pattern PubMed 15221771. Source: RGD autophagy Inferred from sequence or structural similarity. Source: UniProtKB chronic inflammatory response Inferred from expression pattern Ref.1. Source: RGD induction of apoptosis Inferred from sequence or structural similarity. Source: UniProtKB innate immune response Inferred from electronic annotation. Source: UniProtKB-KW leukocyte migration involved in inflammatory response Inferred from sequence or structural similarity. Source: UniProtKB neutrophil aggregation Inferred from sequence or structural similarity. Source: UniProtKB neutrophil chemotaxis Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of inflammatory response Inferred from sequence or structural similarity. Source: UniProtKB response to ethanol Inferred from expression pattern PubMed 17207109. Source: RGD response to lipopolysaccharide Inferred from expression pattern PubMed 17207109. Source: RGD response to zinc ion Inferred from expression pattern PubMed 19111725. Source: RGD wound healing Inferred from expression pattern PubMed 15943814. Source: RGD
Cellular_component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell cytoskeleton Inferred from electronic annotation. Source: UniProtKB-SubCell extracellular space Inferred from direct assay PubMed 15221771. Source: RGD plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	antioxidant activity Inferred from electronic annotation. Source: UniProtKB-KW calcium ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Initiator methionine	1	1	Removed Ref.2
	Chain	2 – 89	88	Protein S100-A8		PRO_0000143995
Regions
	Domain	13 – 48	36	EF-hand 1
	Domain	46 – 81	36	EF-hand 2
	Calcium binding	20 – 33	14	1; low affinity Potential
	Calcium binding	59 – 70	12	2; high affinity Potential
Sites
	Metal binding	17	1	Zinc By similarity
	Metal binding	27	1	Zinc By similarity
	Metal binding	83	1	Zinc By similarity
Amino acid modifications
	Modified residue	2	1	N-acetylalanine Ref.2
	Modified residue	42	1	S-nitrosocysteine By similarity
Experimental info
	Sequence conflict	73	1	V → A in AAA41637. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	P50115 [UniParc]. Last modified January 23, 2007. Version 3. Checksum: 6AC1AFAF3429B01E	FASTA	89	10,239
	10 20 30 40 50 60 MATELEKALS NVIEVYHNYS GIKGNHHALY RDDFRKMVTT ECPQFVQNKN TESLFKELDV 70 80 NSDNAINFEE FLVLVIRVGV AAHKDSHKE

References

[1]	"Expression and cloning of migration inhibitory factor-related protein (MRP)8 and MRP14 in arthritis-susceptible rats." Imamichi T., Uchida I., Wahl S.M., McCartney-Francis N. Biochem. Biophys. Res. Commun. 194:819-825(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: Lewis/N. Tissue: Peritoneal cavity.
[2]	"Identification of posttranslational modifications and cDNA sequencing errors in the rat S100 proteins MRP8 and 14 using electrospray ionization mass spectrometry." Raftery M.J., Geczy C.L. Anal. Biochem. 258:285-292(1998) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-89, MASS SPECTROMETRY, ACETYLATION AT ALA-2. Tissue: Spleen.
[3]	"Dynamic mobility of immunological cells expressing S100A8 and S100A9 in vivo: a variety of functional roles of the two proteins as regulators in acute inflammatory reaction." Koike A., Arai S., Yamada S., Nagae A., Saita N., Itoh H., Uemoto S., Totani M., Ikemoto M. Inflammation 35:409-419(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	L18891 mRNA. Translation: AAA41637.1.
IPI	IPI00231370.
PIR	JN0685.
RefSeq	NP_446274.2. NM_053822.2.
UniGene	Rn.31839.
3D structure databases
ProteinModelPortal	P50115.
SMR	P50115. Positions 1-89.
ModBase	Search...
Protein-protein interaction databases
STRING	10116.ENSRNOP00000015473.
Proteomic databases
PaxDb	P50115.
PRIDE	P50115.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSRNOT00000015473; ENSRNOP00000015473; ENSRNOG00000011557.
GeneID	116547.
KEGG	rno:116547.
Organism-specific databases
CTD	6279.
RGD	620265. S100a8.
Phylogenomic databases
eggNOG	NOG39611.
GeneTree	ENSGT00660000095419.
HOGENOM	HOG000246968.
HOVERGEN	HBG001479.
InParanoid	P50115.
OMA	KDADTWF.
OrthoDB	EOG4V9TS7.
Gene expression databases
Genevestigator	P50115.
GermOnline	ENSRNOG00000011557. Rattus norvegicus.
Family and domain databases
Gene3D	1.10.238.10. 1 hit.
InterPro	IPR011992. EF-hand-like_dom. IPR018247. EF_Hand_1_Ca_BS. 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. 1 hit. PS50222. EF_HAND_2. 1 hit. PS00303. S100_CABP. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	619165.

Entry information

Entry name

S10A8_RAT

Accession

Primary (citable) accession number: P50115

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	January 23, 2007
Last modified:	May 1, 2013
This is version 102 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program