Q9Y6Y9 (LY96_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Lymphocyte antigen 96
Short name=Ly-96

Alternative name(s):
ESOP-1
Protein MD-2

Gene names

Name:	LY96
Synonyms:	ESOP1, MD2

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 › Dipnotetrapodomorpha › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Boreoeutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	160 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	Cooperates with TLR4 in the innate immune response to bacterial lipopolysaccharide (LPS), and with TLR2 in the response to cell wall components from Gram-positive and Gram-negative bacteria. Enhances TLR4-dependent activation of NF-kappa-B. Cells expressing both MD2 and TLR4, but not TLR4 alone, respond to LPS.
Subunit structure	Heterogeneous homopolymer formed from homodimers; disulfide-linked. Belongs to the lipopolysaccharide (LPS) receptor, a multi-protein complex containing at least CD14, LY96 and TLR4. Binds to the extracellular domains of TLR2 and TLR4. Ligand binding induces interaction with TLR4 and oligomerization of the complex. Ref.7 Ref.8 Ref.9 Ref.11
Subcellular location	Secreted › extracellular space.
Post-translational modification	N-glycosylated; high-mannose. Ref.8 Ref.11

Ontologies

Keywords
Biological process	Immunity Inflammatory response Innate immunity
Cellular component	Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Signal
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	I-kappaB kinase/NF-kappaB signaling Traceable author statement. Source: Reactome MyD88-dependent toll-like receptor signaling pathway Traceable author statement. Source: Reactome MyD88-independent toll-like receptor signaling pathway Traceable author statement. Source: Reactome TRIF-dependent toll-like receptor signaling pathway Traceable author statement. Source: Reactome cell surface receptor signaling pathway Traceable author statement Ref.1. Source: ProtInc cellular defense response Traceable author statement Ref.1. Source: ProtInc detection of lipopolysaccharide Inferred from direct assay PubMed 19252480. Source: UniProtKB inflammatory response Inferred from electronic annotation. Source: UniProtKB-KW innate immune response Traceable author statement. Source: Reactome lipopolysaccharide-mediated signaling pathway Inferred from direct assay PubMed 19252480. Source: GOC positive regulation of lipopolysaccharide-mediated signaling pathway Inferred from electronic annotation. Source: Ensembl response to lipopolysaccharide Inferred from direct assay PubMed 12594207. Source: MGI toll-like receptor 2 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 3 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 4 signaling pathway Traceable author statement. Source: Reactome toll-like receptor TLR1:TLR2 signaling pathway Traceable author statement. Source: Reactome toll-like receptor TLR6:TLR2 signaling pathway Traceable author statement. Source: Reactome toll-like receptor signaling pathway Traceable author statement. Source: Reactome
Cellular_component	endosome membrane Traceable author statement. Source: Reactome extracellular space Inferred from electronic annotation. Source: UniProtKB-SubCell lipopolysaccharide receptor complex Inferred from direct assay PubMed 19252480. Source: UniProtKB plasma membrane Traceable author statement. Source: Reactome
Molecular_function	coreceptor activity Traceable author statement Ref.1. Source: ProtInc lipopolysaccharide receptor activity Inferred from direct assay PubMed 19252480. Source: UniProtKB protein binding Inferred from physical interaction PubMed 19252480. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
TLR4	O00206	3	EBI-1539247,EBI-528701

Alternative products

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

Isoform 1 (identifier: Q9Y6Y9-1)

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: Q9Y6Y9-2)

The sequence of this isoform differs from the canonical sequence as follows:
     38-68: DKMQYPISINVNPCIELKRSKGLLHIFYIPR → G

Note: No experimental confirmation available. Gene prediction based on EST data.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 18

18

Potential

Chain

19 – 160

142

Lymphocyte antigen 96

PRO_0000018619

Regions

Region

119 – 123

5

Interaction with lipopolysaccharide

Amino acid modifications

Glycosylation

26

1

N-linked (GlcNAc...) Ref.11

Glycosylation

114

1

N-linked (GlcNAc...) Ref.11

Disulfide bond

25 ↔ 51

Ref.8 Ref.9 Ref.11

Disulfide bond

37 ↔ 148

Ref.8 Ref.9 Ref.11

Disulfide bond

95 ↔ 105

Ref.8 Ref.9 Ref.11

Natural variations

Alternative sequence

38 – 68

31

DKMQY…FYIPR → G in isoform 2.

VSP_055045

Natural variant

56

1

R → G. Ref.1 Ref.2 Ref.3 Ref.4 Ref.6
Corresponds to variant rs6472812 [ dbSNP | Ensembl ].

VAR_050030

Natural variant

157

1

P → S.
Corresponds to variant rs11466004 [ dbSNP | Ensembl ].

VAR_024532

Experimental info

Mutagenesis

95

1

C → Y: Abolishes LPS-response. Ref.3

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

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.

.

.

.

.

.

160

Helix Strand Turn

Details...

Beta strand

22 – 26

5

Beta strand

28 – 36

9

Beta strand

38 – 40

3

Beta strand

45 – 50

6

Beta strand

57 – 65

9

Beta strand

75 – 82

8

Beta strand

90 – 93

4

Beta strand

97 – 101

5

Helix

103 – 106

4

Beta strand

113 – 121

9

Beta strand

129 – 139

11

Turn

140 – 143

4

Beta strand

144 – 155

12

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified May 18, 2010. Version 2. Checksum: 0F92AFF583637C6B	FASTA	160	18,546
	10 20 30 40 50 60 MLPFLFFSTL FSSIFTEAQK QYWVCNSSDA SISYTYCDKM QYPISINVNP CIELKRSKGL 70 80 90 100 110 120 LHIFYIPRRD LKQLYFNLYI TVNTMNLPKR KEVICRGSDD DYSFCRALKG ETVNTTISFS 130 140 150 160 FKGIKFSKGK YKCVVEAISG SPEEMLFCLE FVILHQPNSN
	Isoform 2 [UniParc]. Checksum: 7D92D168412B21C7	FASTA	130	14,933
	10 20 30 40 50 60 MLPFLFFSTL FSSIFTEAQK QYWVCNSSDA SISYTYCGRD LKQLYFNLYI TVNTMNLPKR 70 80 90 100 110 120 KEVICRGSDD DYSFCRALKG ETVNTTISFS FKGIKFSKGK YKCVVEAISG SPEEMLFCLE 130 FVILHQPNSN

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4." Shimazu R., Akashi S., Ogata H., Nagai Y., Fukudome K., Miyake K., Kimoto M. J. Exp. Med. 189:1777-1782(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT GLY-56. Tissue: Uterus.
[2]	"ESOP-1, a secreted protein expressed in the hematopoietic, nervous, and reproductive systems of embryonic and adult mice." Kato K., Morrison A.M., Nakano T., Tashiro K., Honjo T. Blood 96:362-364(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT GLY-56.
[3]	"Molecular genetic analysis of an endotoxin nonresponder mutant cell line. A point mutation in a conserved region of MD-2 abolishes endotoxin-induced signaling." Schromm A.B., Lien E., Henneke P., Chow J.C., Yoshimura A., Heine H., Latz E., Monks B.G., Schwartz D.A., Miyake K., Golenbock D.T. J. Exp. Med. 194:79-88(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), MUTAGENESIS OF CYS-95, VARIANT GLY-56.
[4]	"Natural selection in the TLR-related genes in the course of primate evolution." Nakajima T., Ohtani H., Satta Y., Uno Y., Akari H., Ishida T., Kimura A. Immunogenetics 60:727-735(2008) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT GLY-56.
[5]	"DNA sequence and analysis of human chromosome 8." Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M., Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S., Asakawa T. , Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A., Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III, Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P., Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H., Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B., O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K., Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L., Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G., Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W., Platzer M., Shimizu N., Lander E.S. Nature 439:331-335(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"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] (ISOFORM 1), VARIANT GLY-56. Tissue: Liver.
[7]	"MD-2 enables Toll-like receptor 2 (TLR2)-mediated responses to lipopolysaccharide and enhances TLR2-mediated responses to Gram-positive and Gram-negative bacteria and their cell wall components." Dziarski R., Wang Q., Miyake K., Kirschning C.J., Gupta D. J. Immunol. 166:1938-1944(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TLR2 AND TLR4.
[8]	"Secreted MD-2 is a large polymeric protein that efficiently confers lipopolysaccharide sensitivity to Toll-like receptor 4." Visintin A., Mazzoni A., Spitzer J.A., Segal D.M. Proc. Natl. Acad. Sci. U.S.A. 98:12156-12161(2001) [PubMed] [Europe PMC] [Abstract] Cited for: DISULFIDE BONDS, GLYCOSYLATION.
[9]	"The role of disulfide bonds in the assembly and function of MD-2." Mullen G.E.D., Kennedy M.N., Visintin A., Mazzoni A., Leifer C.A., Davies D.R., Segal D.M. Proc. Natl. Acad. Sci. U.S.A. 100:3919-3924(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERCHAIN DISULFIDE BOND.
[10]	"Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran." Kim H.M., Park B.S., Kim J.-I., Kim S.E., Lee J., Oh S.C., Enkhbayar P., Matsushima N., Lee H., Yoo O.J., Lee J.-O. Cell 130:906-917(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 19-158 IN COMPLEX WITH TLR4 AND LIPOPOLYSACCHARIDE ANALOG.
[11]	"Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa." Ohto U., Fukase K., Miyake K., Satow Y. Science 316:1632-1634(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 17-160 IN COMPLEX WITH LIPID IV-A, DISULFIDE BONDS, GLYCOSYLATION AT ASN-26 AND ASN-114.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AB018549 mRNA. Translation: BAA78717.1.
AF168121 mRNA. Translation: AAF89635.1.
AB446498 mRNA. Translation: BAG55275.1.
AC022868 Genomic DNA. No translation available.
AC087672 Genomic DNA. No translation available.
BC020690 mRNA. Translation: AAH20690.1.

CCDS

CCDS6216.1.

RefSeq

NP_001182726.1. NM_001195797.1.
NP_056179.3. NM_015364.4.

UniGene

Hs.726603.

3D structure databases

PDBe
RCSB-PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1T2Z	model	-	A	19-160	[»]
2E56	X-ray	2.00	A	17-160	[»]
2E59	X-ray	2.21	A	17-160	[»]
2Z65	X-ray	2.70	C/D	19-158	[»]
3FXI	X-ray	3.10	C/D	19-160	[»]
3ULA	X-ray	3.60	B/D	19-158	[»]
4G8A	X-ray	2.40	C/D	17-160	[»]

ProteinModelPortal

Q9Y6Y9.

SMR

Q9Y6Y9. Positions 17-160.

ModBase

Search...

MobiDB

Search...

Protein-protein interaction databases

BioGrid

117170. 4 interactions.

DIP

DIP-38571N.

IntAct

Q9Y6Y9. 2 interactions.

STRING

9606.ENSP00000284818.

Chemistry

ChEMBL

CHEMBL3038513.

PTM databases

PhosphoSite

Q9Y6Y9.

Polymorphism databases

DMDM

296434574.

Proteomic databases

MaxQB

Q9Y6Y9.

PaxDb

Q9Y6Y9.

PRIDE

Q9Y6Y9.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000284818; ENSP00000284818; ENSG00000154589.
ENST00000518893; ENSP00000430533; ENSG00000154589.

GeneID

23643.

KEGG

hsa:23643.

UCSC

uc003yad.3. human.

Organism-specific databases

CTD

23643.

GeneCards

GC08P074953.

HGNC

HGNC:17156. LY96.

HPA

HPA053060.

MIM

605243. gene.

neXtProt

NX_Q9Y6Y9.

PharmGKB

PA134924906.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG46291.

HOGENOM

HOG000001152.

HOVERGEN

HBG032514.

InParanoid

Q9Y6Y9.

KO

K05400.

OMA

IPRRDIK.

OrthoDB

EOG7QG45N.

PhylomeDB

Q9Y6Y9.

TreeFam

TF335876.

Enzyme and pathway databases

Reactome

REACT_6900. Immune System.

Gene expression databases

ArrayExpress

Q9Y6Y9.

Bgee

Q9Y6Y9.

CleanEx

HS_LY96.

Genevestigator

Q9Y6Y9.

Family and domain databases

InterPro

IPR014756. Ig_E-set.
IPR003172. ML_dom.
[Graphical view]

Pfam

PF02221. E1_DerP2_DerF2. 1 hit.
[Graphical view]

SMART

SM00737. ML. 1 hit.
[Graphical view]

SUPFAM

SSF81296. SSF81296. 1 hit.

ProtoNet

Search...

Other

EvolutionaryTrace

Q9Y6Y9.

GeneWiki

Lymphocyte_antigen_96.

GenomeRNAi

23643.

NextBio

46449.

PRO

Q9Y6Y9.

SOURCE

Search...

Entry information

Entry name

LY96_HUMAN

Accession

Primary (citable) accession number: Q9Y6Y9
Secondary accession number(s): B3Y6A5, E5RJJ7

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 27, 2002
Last sequence update:	May 18, 2010
Last modified:	July 9, 2014
This is version 124 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.