Reviewed, UniProtKB/Swiss-Prot Q15109 (RAGE_HUMAN)

Names and origin

Protein names

Recommended name:
    Advanced glycosylation end product-specific receptor
Alternative name(s):
    Receptor for advanced glycosylation end products

Gene names

Name:	AGER
Synonyms:	RAGE

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	404 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	Mediates interactions of advanced glycosylation end products (AGE). These are nonenzymatically glycosylated proteins which accumulate in vascular tissue in aging and at an accelerated rate in diabetes. Acts as a mediator of both acute and chronic vascular inflammation in conditions such as atherosclerosis and in particular as a complication of diabetes. AGE/RAGE signaling plays an important role in regulating the production/expression of TNF-alpha, oxidative stress, and endothelial dysfunction in type 2 diabetes. Interaction with S100A12 on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key proinflammatory mediators. Interaction with S100B after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53/TP53 signaling By similarity. Receptor for amyloid beta peptide. Contributes to the translocation of amyloid-beta peptide (ABPP) across the cell membrane from the extracellular to the intracellular space in cortical neurons. ABPP-initiated RAGE signaling, especially stimulation of p38 mitogen-activated protein kinase (MAPK), has the capacity to drive a transport system delivering ABPP as a complex with RAGE to the intraneuronal space.
Subunit structure	Interacts with S100B, S100A1 and APP By similarity. Interacts with S100A12.
Subcellular location	Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted.
Tissue specificity	Endothelial cells.
Sequence similarities	Contains 2 Ig-like C2-type (immunoglobulin-like) domains. Contains 1 Ig-like V-type (immunoglobulin-like) domain.

Ontologies

Keywords
Biological process	Inflammatory response
Cellular component	Cell membrane Membrane Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Immunoglobulin domain Repeat Signal Transmembrane
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	cell surface receptor linked signal transduction Traceable author statement. Source: ProtInc inflammatory response Traceable author statement. Source: ProtInc
Cellular component	integral to plasma membrane Ref.1 Traceable author statement. Source: ProtInc
Molecular function	protein binding Ref.10 Inferred from physical interaction. Source: UniProtKB transmembrane receptor activity Ref.1 Traceable author statement. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
GRB2	P62993	1	EBI-1646426,EBI-401755
NCK1	P16333	1	EBI-1646426,EBI-389883
S100P	P25815	1	EBI-1646426,EBI-743700

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q15109-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q15109-2)

Also known as: RAGESEC;

The sequence of this isoform differs from the canonical sequence as follows:
     54-67: Missing.
     275-404: GVPLPLPPSP...EAGESSTGGP → VSDLERGAGR...ACRTESVGGT

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 22

22

Potential

Chain

23 – 404

382

Advanced glycosylation end product-specific receptor

PRO_0000014923

Regions

Topological domain

23 – 342

320

Extracellular Potential

Transmembrane

343 – 363

21

Potential

Topological domain

364 – 404

41

Cytoplasmic Potential

Domain

23 – 116

94

Ig-like V-type

Domain

124 – 221

98

Ig-like C2-type 1

Domain

227 – 317

91

Ig-like C2-type 2

Compositional bias

380 – 384

5

Poly-Glu

Amino acid modifications

Glycosylation

25

1

N-linked (GlcNAc...) Potential

Glycosylation

81

1

N-linked (GlcNAc...) Potential

Disulfide bond

38 ↔ 99

Potential

Disulfide bond

144 ↔ 208

Potential

Disulfide bond

259 ↔ 301

Potential

Natural variations

Alternative sequence

54 – 67

14

Missing in isoform 2.

VSP_002551

Alternative sequence

275 – 404

130

GVPLP…STGGP → VSDLERGAGRTRRGGANCRL CGRIRAGNSSPGPGDPGRPG DSRPAHWGHLVAKAATPRRG EEGPRKPGGRGGACRTESVG GT in isoform 2.

VSP_002552

Natural variant

82

1

G → S: dbSNP rs2070600. Ref.7

VAR_024500

Natural variant

100

1

Q → R

VAR_011338

Experimental info

Sequence conflict

1

1

M → G in AAA03574. Ref.1

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

404

Helix Strand Turn

Details...

Beta strand

241 – 244

4

Beta strand

247 – 249

3

Beta strand

254 – 258

5

Beta strand

272 – 277

6

Beta strand

284 – 290

7

Turn

293 – 295

3

Beta strand

297 – 300

4

Beta strand

316 – 320

5

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified November 1, 1997. Version 1. Checksum: 0D584C436C30CCE7	FASTA	404	42,803
	10 20 30 40 50 60 MAAGTAVGAW VLVLSLWGAV VGAQNITARI GEPLVLKCKG APKKPPQRLE WKLNTGRTEA 70 80 90 100 110 120 WKVLSPQGGG PWDSVARVLP NGSLFLPAVG IQDEGIFRCQ AMNRNGKETK SNYRVRVYQI 130 140 150 160 170 180 PGKPEIVDSA SELTAGVPNK VGTCVSEGSY PAGTLSWHLD GKPLVPNEKG VSVKEQTRRH 190 200 210 220 230 240 PETGLFTLQS ELMVTPARGG DPRPTFSCSF SPGLPRHRAL RTAPIQPRVW EPVPLEEVQL 250 260 270 280 290 300 VVEPEGGAVA PGGTVTLTCE VPAQPSPQIH WMKDGVPLPL PPSPVLILPE IGPQDQGTYS 310 320 330 340 350 360 CVATHSSHGP QESRAVSISI IEPGEEGPTA GSVGGSGLGT LALALGILGG LGTAALLIGV 370 380 390 400 ILWQRRQRRG EERKAPENQE EEEERAELNQ SEEPEAGESS TGGP
	Isoform 2 (RAGESEC). Checksum: 35DDF66A13E39B38	FASTA	342	36,193
	10 20 30 40 50 60 MAAGTAVGAW VLVLSLWGAV VGAQNITARI GEPLVLKCKG APKKPPQRLE WKLGGGPWDS 70 80 90 100 110 120 VARVLPNGSL FLPAVGIQDE GIFRCQAMNR NGKETKSNYR VRVYQIPGKP EIVDSASELT 130 140 150 160 170 180 AGVPNKVGTC VSEGSYPAGT LSWHLDGKPL VPNEKGVSVK EQTRRHPETG LFTLQSELMV 190 200 210 220 230 240 TPARGGDPRP TFSCSFSPGL PRHRALRTAP IQPRVWEPVP LEEVQLVVEP EGGAVAPGGT 250 260 270 280 290 300 VTLTCEVPAQ PSPQIHWMKD VSDLERGAGR TRRGGANCRL CGRIRAGNSS PGPGDPGRPG 310 320 330 340 DSRPAHWGHL VAKAATPRRG EEGPRKPGGR GGACRTESVG GT

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins." Neeper M., Schmidt A.M., Brett J., Yan S.D., Wang F., Pan Y.C., Elliston K., Stern D., Shaw A. J. Biol. Chem. 267:14998-15004(1992) [PubMed: 1378843] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Lung.
[2]	"Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a notch homolog, human counterpart of mouse mammary tumor gene int-3." Sugaya K., Fukagawa T., Matsumoto K., Mita K., Takahashi E., Ando A., Inoko H., Ikemura T. Genomics 23:408-419(1994) [PubMed: 7835890] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
[3]	"Molecular heterogeneity of the receptor for advanced glycation endproducts." Abedin M.J., Yonekura H., Migita H., Karasawa J., Yamamoto Y., Yamamoto H. Submitted (JAN-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT ARG-100.
[4]	"cDNA cloning of a novel secreted isoform of the human receptor for advanced glycation end products (RAGE) and characterization of cells co-expressing cell-surface scavenger receptors and Swedish mutant amyloid precursor protein." Malherbe P., Richards J., Gaillard H., Thompson A., Diener C., Schuler A., Huber G. Submitted (MAY-1999) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
[5]	"Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse." Xie T., Rowen L., Aguado B., Ahearn M.E., Madan A., Qin S., Campbell R.D., Hood L. Genome Res. 13:2621-2636(2003) [PubMed: 14656967] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"The DNA sequence and analysis of human chromosome 6." Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S. Nature 425:805-811(2003) [PubMed: 14574404] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT SER-82.
[8]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Lung.
[9]	"Effects of novel polymorphisms in the RAGE gene on transcriptional regulation and their association with diabetic retinopathy." Hudson B.I., Stickland M.H., Futers T.S., Grant P.J. Diabetes 50:1505-1511(2001) [PubMed: 11375354] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-12.
[10]	"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: 19386136] [Abstract] Cited for: INTERACTION WITH S100A12.
[11]	"RAGE-dependent signaling in microglia contributes to neuroinflammation, A{beta} accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease." Fang F., Lue L.-F., Yan S., Xu H., Luddy J.S., Chen D., Walker D.G., Stern D.M., Yan S., Schmidt A.M., Chen J.X., Yan S.S. FASEB J. 0:0-0(2009) [PubMed: 19906677] [Abstract] Cited for: FUNCTION.
[12]	"Solution structure of the third IG-like domain from human advanced glycosylation end product-specific receptor." RIKEN structural genomics initiative (RSGI) Submitted (APR-2008) to the PDB data bank Cited for: STRUCTURE BY NMR OF 235-323.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M91211 mRNA. Translation: AAA03574.1.
D28769 Genomic DNA. Translation: BAA05958.1.
AB036432 mRNA. Translation: BAA89369.1.
AJ133822 mRNA. Translation: CAB43108.1.
U89336 Genomic DNA. Translation: AAB47491.1.
AL662830 Genomic DNA. Translation: CAI17535.1.
AL662830 Genomic DNA. Translation: CAI17536.1.
AL662884 Genomic DNA. Translation: CAI18354.1.
AL662884 Genomic DNA. Translation: CAI18355.1.
AL845464 Genomic DNA. Translation: CAI41809.1.
AL845464 Genomic DNA. Translation: CAI41810.1.
BX284686 Genomic DNA. Translation: CAM26223.1.
BX927239 Genomic DNA. Translation: CAQ06596.1.
CR933878 Genomic DNA. Translation: CAQ09624.1.
CR812478 Genomic DNA. Translation: CAQ10699.1.
CH471081 Genomic DNA. Translation: EAX03610.1.
BC020669 mRNA. Translation: AAH20669.1.
AF208289 Genomic DNA. Translation: AAG35728.1.

IPI

IPI00014810.
IPI00220335.

PIR

I61596.

RefSeq

NP_001127.1.
NP_751947.1.

UniGene

Hs.534342

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1PWI	model	-	A	1-404	[»]
2BJP	model	-	A	1-404	[»]
2E5E	NMR	-	A	23-121	[»]
2ENS	NMR	-	A	235-323	[»]
3CJJ	X-ray	1.85	A	23-240	[»]

SMR

Q15109. Positions 22-323.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q15109. 3 interactions.

STRING

Q15109.

Proteomic databases

PRIDE

Q15109.

Genome annotation databases

Ensembl

ENST00000375070; ENSP00000364211; ENSG00000204305; Homo sapiens. [Genome view]
ENST00000375076; ENSP00000364217; ENSG00000204305; Homo sapiens. [Genome view]
ENST00000383280; ENSP00000372767; ENSG00000206320; Homo sapiens. [Genome view]
ENST00000411644; ENSP00000410213; ENSG00000234729; Homo sapiens. [Genome view]
ENST00000436456; ENSP00000397227; ENSG00000234729; Homo sapiens. [Genome view]
ENST00000436776; ENSP00000407164; ENSG00000237405; Homo sapiens. [Genome view]
ENST00000447921; ENSP00000395812; ENSG00000237405; Homo sapiens. [Genome view]
ENST00000451115; ENSP00000401068; ENSG00000206320; Homo sapiens. [Genome view]
ENST00000453042; ENSP00000396679; ENSG00000229058; Homo sapiens. [Genome view]
ENST00000456918; ENSP00000409457; ENSG00000229058; Homo sapiens. [Genome view]

GeneID

177.

KEGG

hsa:177.

UCSC

uc003oal.1. human.
uc003oan.1. human.

Organism-specific databases

CTD

177.

GeneCards

GC06M032256.

H-InvDB

HIX0005749.
HIX0057955.
HIX0058132.

HGNC

HGNC:320. AGER.

HPA

CAB011682.

MIM

600214. gene.

PharmGKB

PA24617.

GenAtlas

Search...

Phylogenomic databases

HOVERGEN

Q15109.

InParanoid

Q15109.

PhylomeDB

Q15109.

Enzyme and pathway databases

Pathway_Interaction_DB

amb2_neutrophils_pathway. amb2 Integrin signaling.

Gene expression databases

CleanEx

HS_AGER.
HS_RAGE.

Genevestigator

Q15109.

GermOnline

ENSG00000204305. Homo sapiens.

Family and domain databases

InterPro

IPR013162. CD80_C2-set.
IPR007110. Ig-like.
IPR013783. Ig-like_fold.
IPR003006. Ig/MHC_CS.
IPR003599. Ig_sub.
IPR003598. Ig_sub2.
[Graphical view]

Gene3D

G3DSA:2.60.40.10. Ig-like_fold. 2 hits.

Pfam

PF08205. C2-set_2. 1 hit.
[Graphical view]

SMART

SM00409. IG. 1 hit.
SM00408. IGc2. 1 hit.
[Graphical view]

PROSITE

PS50835. IG_LIKE. 3 hits.
PS00290. IG_MHC. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

716.

SOURCE

Search...

Entry information

Entry name

RAGE_HUMAN

Accession

Primary (citable) accession number: Q15109
Secondary accession number(s): A2BFI7 , B0V176, Q15279, Q9H2X7, Q9Y3R3

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	November 1, 1997
Last modified:	February 9, 2010
This is version 103 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.