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Protein

Hepatitis A virus cellular receptor 2

Gene

HAVCR2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Cell surface receptor implicated in modulating innate and adaptive immune responses. Generally accepted to have an inhibiting function. Reports on stimulating functions suggest that the activity may be influenced by the cellular context and/or the respective ligand (PubMed:24825777). Regulates macrophage activation (PubMed:11823861). Inhibits T-helper type 1 lymphocyte (Th1)-mediated auto- and alloimmune responses and promotes immunological tolerance (PubMed:14556005). In CD8+ cells attenuates TCR-induced signaling, specifically by blocking NF-kappaB and NFAT promoter activities resulting in the loss of IL-2 secretion. The function may implicate its association with LCK proposed to impair phosphorylation of TCR subunits, and/or LGALS9-dependent recruitment of PTPRC to the immunological synapse (PubMed:24337741, PubMed:26492563). In contrast, shown to activate TCR-induced signaling in T-cells probably implicating ZAP70, LCP2, LCK and FYN (By similarity). Expressed on Treg cells can inhibit Th17 cell responses (PubMed:24838857). Receptor for LGALS9 (PubMed:16286920, PubMed:24337741). Binding to LGALS9 is believed to result in suppression of T-cell responses; the resulting apoptosis of antigen-specific cells may implicate HAVCR2 phosphorylation and disruption of its association with BAG6. Binding to LGALS9 is proposed to be involved in innate immune response to intracellular pathogens. Expressed on Th1 cells interacts with LGALS9 expressed on Mycobacterium tuberculosis-infected macrophages to stimulate antibactericidal activity including IL-1 beta secretion and to restrict intracellular bacterial growth (By similarity). However, the function as receptor for LGALS9 has been challenged (PubMed:23555261). Also reported to enhance CD8+ T-cell responses to an acute infection such as by Listeria monocytogenes (By similarity). Receptor for phosphatidylserine (PtSer); PtSer-binding is calcium-dependent. May recognize PtSer on apoptotic cells leading to their phagocytosis. Mediates the engulfment of apoptotic cells by dendritic cells. Expressed on T-cells, promotes conjugation but not engulfment of apoptotic cells. Expressed on dendritic cells (DCs) positively regulates innate immune response and in synergy with Toll-like receptors promotes secretion of TNF-alpha. In tumor-imfiltrating DCs suppresses nucleic acid-mediated innate immune repsonse by interaction with HMGB1 and interfering with nucleic acid-sensing and trafficking of nucleid acids to endosomes (By similarity). Expressed on natural killer (NK) cells acts as a coreceptor to enhance IFN-gamma production in response to LGALS9 (PubMed:22323453). In contrast, shown to suppress NK cell-mediated cytotoxicity (PubMed:22383801). Negatively regulates NK cell function in LPS-induced endotoxic shock (By similarity).By similarity1 Publication7 Publications

Caution

Experimental results based on the injection of HAVCR2/TIM-3 antibodies or use of HAVCR2/TIM-3-Fc fusion proteins can reflect changes in the activity of several cell types and pathways as HAVCR2/TIM-3 is expressed by multiple immune cell types.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei111PhosphatidylserineBy similarity1
Metal bindingi116Calcium; via carbonyl oxygenBy similarity1
Binding sitei118Phosphatidylserine; via amide nitrogenBy similarity1
Metal bindingi119CalciumBy similarity1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Biological processAdaptive immunity, Immunity, Inflammatory response, Innate immunity
LigandMetal-binding

Enzyme and pathway databases

ReactomeiR-HSA-451927 Interleukin-2 family signaling

Names & Taxonomyi

Protein namesi
Recommended name:
Hepatitis A virus cellular receptor 2
Short name:
HAVcr-2
Alternative name(s):
T-cell immunoglobulin and mucin domain-containing protein 3
Short name:
TIMD-3
T-cell immunoglobulin mucin receptor 3
Short name:
TIM-3
T-cell membrane protein 3
Gene namesi
Name:HAVCR2
Synonyms:TIM3, TIMD3
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 5

Organism-specific databases

EuPathDBiHostDB:ENSG00000135077.8
HGNCiHGNC:18437 HAVCR2
MIMi606652 gene
neXtProtiNX_Q8TDQ0

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini22 – 202ExtracellularSequence analysisAdd BLAST181
Transmembranei203 – 223HelicalSequence analysisAdd BLAST21
Topological domaini224 – 301CytoplasmicSequence analysisAdd BLAST78

Keywords - Cellular componenti

Cell junction, Membrane

Pathology & Biotechi

Involvement in diseasei

May be involved in T-cell exhaustion associated with chronic viral infections such as with human immunodeficiency virus (HIV) and hepatitic C virus (HCV).2 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi265Y → A: Abolishes TCR-induced NFAT activation; when associated with A-272. 1 Publication1
Mutagenesisi265Y → E: No effect on TCR-induced NFAT activation (phosphomimetic mutation); when associated with E-272. 1 Publication1
Mutagenesisi272Y → A: Abolishes TCR-induced NFAT activation; when associated with A-265. 1 Publication1
Mutagenesisi272Y → E: No effect on TCR-induced NFAT activation (phosphomimetic mutation); when associated with E-265. 1 Publication1

Organism-specific databases

DisGeNETi84868
OpenTargetsiENSG00000135077
PharmGKBiPA134883425

Polymorphism and mutation databases

BioMutaiHAVCR2
DMDMi311033536

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 21Sequence analysisAdd BLAST21
ChainiPRO_000004210122 – 301Hepatitis A virus cellular receptor 2Add BLAST280

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi38 ↔ 110PROSITE-ProRule annotationBy similarity
Disulfide bondi52 ↔ 63PROSITE-ProRule annotationBy similarity
Disulfide bondi58 ↔ 109PROSITE-ProRule annotationBy similarity
Glycosylationi145O-linked (GalNAc...) threonine1 Publication1
Glycosylationi172N-linked (GlcNAc...) asparagineSequence analysis1
Modified residuei265Phosphotyrosine; by ITK1 Publication1

Post-translational modificationi

O-glycosylated with core 1 or possibly core 8 glycans.1 Publication
Phosphorylated on tyrosine residues; modestly increased after TCR/CD28 stimulation. Can be phosphorylated in the cytoplasmatic domain by FYN (By similarity). Phosphorylation at Tyr-265 is increased by stimulation with ligand LGALS9.By similarity2 Publications

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

PaxDbiQ8TDQ0
PeptideAtlasiQ8TDQ0
PRIDEiQ8TDQ0
ProteomicsDBi74319
74320 [Q8TDQ0-2]

PTM databases

GlyConnecti712
iPTMnetiQ8TDQ0
PhosphoSitePlusiQ8TDQ0
UniCarbKBiQ8TDQ0

Expressioni

Tissue specificityi

Expressed in T-helper type 1 (Th1) lymphocytes. Expressed on regulatory T (Treg) cells after TCR stimulation. Expressed in dendritic cells and natural killer (NK) cells. Expressed in epithelial tissues. Expression is increased on CD4+ and CD8+ T-cells in chronic hepatitis C virus (HCV) infection. In progressive HIV-1 infection, expression is up-regulated on HIV-1-specific CD8 T-cells.8 Publications

Gene expression databases

BgeeiENSG00000135077
CleanExiHS_HAVCR2
ExpressionAtlasiQ8TDQ0 baseline and differential
GenevisibleiQ8TDQ0 HS

Organism-specific databases

HPAiCAB026003

Interactioni

Subunit structurei

Interacts with HMGB1; impairs HMGB1 binding to B-DNA and likely HMGB1-mediated innate immume response (By similarity). Interacts with BAG6 (By similarity). Interacts (phosphorylated) with PIK3R1 and PIK3R2. Interacts (not dependent on its phosphorylation status) with FYN (By similarity). Interacts (in basal state T-cells) with VAV1; AKT1/2, LCP2, ZAP70, SYK, PIK3R1, FYN, SH3BP2 and SH2D2A. Interacts (in activated T-cells) with LCK and PLCG (PubMed:26492563, PubMed:24337741).By similarity2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
CEACAM1P136884EBI-11472922,EBI-4314481

Protein-protein interaction databases

BioGridi124313, 72 interactors
DIPiDIP-61459N
IntActiQ8TDQ0, 14 interactors
STRINGi9606.ENSP00000312002

Structurei

Secondary structure

1301
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi26 – 29Combined sources4
Beta strandi34 – 36Combined sources3
Beta strandi44 – 46Combined sources3
Beta strandi51 – 57Combined sources7
Beta strandi60 – 62Combined sources3
Beta strandi64 – 69Combined sources6
Helixi77 – 79Combined sources3
Beta strandi80 – 83Combined sources4
Helixi88 – 90Combined sources3
Beta strandi95 – 97Combined sources3
Helixi102 – 104Combined sources3
Beta strandi106 – 112Combined sources7
Beta strandi121 – 130Combined sources10

3D structure databases

ProteinModelPortaliQ8TDQ0
SMRiQ8TDQ0
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini22 – 124Ig-like V-typeAdd BLAST103

Sequence similaritiesi

Belongs to the immunoglobulin superfamily. TIM family.Curated

Keywords - Domaini

Immunoglobulin domain, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410IJGA Eukaryota
ENOG410YSF7 LUCA
GeneTreeiENSGT00440000039800
HOVERGENiHBG098563
InParanoidiQ8TDQ0
KOiK20414
OMAiGCRFAMP
OrthoDBiEOG091G0MO1
PhylomeDBiQ8TDQ0
TreeFamiTF336163

Family and domain databases

Gene3Di2.60.40.10, 1 hit
InterProiView protein in InterPro
IPR007110 Ig-like_dom
IPR036179 Ig-like_dom_sf
IPR013783 Ig-like_fold
IPR003599 Ig_sub
IPR013106 Ig_V-set
PfamiView protein in Pfam
PF07686 V-set, 1 hit
SMARTiView protein in SMART
SM00409 IG, 1 hit
SUPFAMiSSF48726 SSF48726, 1 hit
PROSITEiView protein in PROSITE
PS50835 IG_LIKE, 1 hit

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8TDQ0-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MFSHLPFDCV LLLLLLLLTR SSEVEYRAEV GQNAYLPCFY TPAAPGNLVP
60 70 80 90 100
VCWGKGACPV FECGNVVLRT DERDVNYWTS RYWLNGDFRK GDVSLTIENV
110 120 130 140 150
TLADSGIYCC RIQIPGIMND EKFNLKLVIK PAKVTPAPTR QRDFTAAFPR
160 170 180 190 200
MLTTRGHGPA ETQTLGSLPD INLTQISTLA NELRDSRLAN DLRDSGATIR
210 220 230 240 250
IGIYIGAGIC AGLALALIFG ALIFKWYSHS KEKIQNLSLI SLANLPPSGL
260 270 280 290 300
ANAVAEGIRS EENIYTIEEN VYEVEEPNEY YCYVSSRQQP SQPLGCRFAM

P
Length:301
Mass (Da):33,394
Last modified:November 2, 2010 - v3
Checksum:i519A5B0D512B6173
GO
Isoform 2 (identifier: Q8TDQ0-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     132-142: AKVTPAPTRQR → GEWTFACHLYE
     143-301: Missing.

Show »
Length:142
Mass (Da):16,149
Checksum:iE2C82D8B5AABC23E
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti101T → I in AAM19100 (Ref. 2) Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_025342140R → L6 PublicationsCorresponds to variant dbSNP:rs1036199Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_017287132 – 142AKVTPAPTRQR → GEWTFACHLYE in isoform 2. 1 PublicationAdd BLAST11
Alternative sequenceiVSP_017288143 – 301Missing in isoform 2. 1 PublicationAdd BLAST159

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF251707 mRNA Translation: AAM19100.1
AY069944 mRNA Translation: AAL55401.1
AK027334 mRNA Translation: BAB55044.1
AK314406 mRNA Translation: BAG37029.1
AC011377 Genomic DNA No translation available.
CH471062 Genomic DNA Translation: EAW61614.1
BC020843 mRNA Translation: AAH20843.1
BC063431 mRNA Translation: AAH63431.1
CCDSiCCDS4333.1 [Q8TDQ0-1]
RefSeqiNP_116171.3, NM_032782.4 [Q8TDQ0-1]
UniGeneiHs.710500

Genome annotation databases

EnsembliENST00000307851; ENSP00000312002; ENSG00000135077 [Q8TDQ0-1]
GeneIDi84868
KEGGihsa:84868
UCSCiuc003lwk.3 human [Q8TDQ0-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiHAVR2_HUMAN
AccessioniPrimary (citable) accession number: Q8TDQ0
Secondary accession number(s): B2RAY2, Q8WW60, Q96K94
Entry historyiIntegrated into UniProtKB/Swiss-Prot: September 27, 2005
Last sequence update: November 2, 2010
Last modified: July 18, 2018
This is version 133 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 5
    Human chromosome 5: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

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