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Hepatitis A virus cellular receptor 2 homolog



Mus musculus (Mouse)
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli


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:18006747). Regulates macrophage activation (PubMed:11823861). Inhibits T-helper type 1 lymphocyte (Th1)-mediated auto- and alloimmune responses and promotes immunological tolerance (PubMed:14556006, PubMed:18006747). 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 (By similarity). In contrast, shown to activate TCR-induced signaling in T-cells probably implicating ZAP70, LCP2, LCK and FYN (PubMed:21807895). Expressed on Treg cells can inhibit Th17 cell responses (By similarity). Receptor for LGALS9. 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 (PubMed:22863785). 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 (PubMed:20937702). However, the function as receptor for LGALS9 has been challenged (By similarity). Also reported to enhance CD8+ T-cell responses to an acute infection such as by Listeria monocytogenes (PubMed:24567532). Receptor for phosphatidylserine (PtSer); PtSer-binding is calcium-dependent (PubMed:20083673). May recognize PtSer on apoptotic cells leading to their phagocytosis. Mediates the engulfment of apoptotic cells by dendritic cells (PubMed:19224762). Expressed on T-cells, promotes conjugation but not engulfment of apoptotic cells (PubMed:20083673). Expressed on dendritic cells (DCs) positively regulates innate immune response and in synergy with Toll-like receptors promotes secretion of TNF-alpha (PubMed:18006747). 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 (PubMed:22842346). Can enhance mast cell production of Th2 cytokines Il-4, IL-6 and IL-13 (PubMed:17620455). Expressed on natural killer (NK) cells acts as a coreceptor to enhance IFN-gamma production in response to LGALS9. In contrast, shown to suppress NK cell-mediated cytotoxicity (By similarity). Negatively regulates NK cell function in LPS-induced endotoxic shock (PubMed:25337993).By similarity1 Publication11 Publications


Belongs to the T-cell and airway phenotype regulator (Tapr) locus, a single chromosomal region that confers reduced T-helper type 2 responsiveness and protects against airway hyperactivity (AHR), the hallmark of human asthma.
In vivo administration of antibody to HAVCR2 enhances the clinical and pathological severity of experimental autoimmune encephalomyelitis (EAE), a Th1-dependent autoimmune disease and increases the number and activation level of macrophages.
Endogenous expression on dendritic cells is proposed to act as a negative regulator of chemotherapy-induced antitumor responses.1 Publication


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei61PhosphatidylserineCombined sources1 Publication1
Binding sitei62Phosphatidylserine; via amide nitrogenCombined sources1 Publication1
Binding sitei112PhosphatidylserineCombined sources1 Publication1
Metal bindingi115Calcium; via carbonyl oxygenCombined sources1 Publication1
Metal bindingi117Calcium; via carbonyl oxygenCombined sources1 Publication1
Binding sitei119Phosphatidylserine; via amide nitrogenCombined sources1 Publication1
Metal bindingi120CalciumCombined sources1 Publication1

GO - Molecular functioni

GO - Biological processi

  • adaptive immune response Source: UniProtKB-KW
  • cellular response to lipopolysaccharide Source: UniProtKB
  • defense response to Gram-positive bacterium Source: UniProtKB
  • inflammatory response Source: UniProtKB-KW
  • innate immune response Source: UniProtKB-KW
  • macrophage activation involved in immune response Source: UniProtKB
  • maternal process involved in female pregnancy Source: UniProtKB
  • natural killer cell tolerance induction Source: MGI
  • negative regulation of defense response to bacterium Source: UniProtKB
  • negative regulation of gene expression Source: MGI
  • negative regulation of granulocyte colony-stimulating factor production Source: MGI
  • negative regulation of immune response to tumor cell Source: UniProtKB
  • negative regulation of immunological synapse formation Source: UniProtKB
  • negative regulation of innate immune response Source: UniProtKB
  • negative regulation of interferon-alpha production Source: MGI
  • negative regulation of interferon-gamma production Source: UniProtKB
  • negative regulation of interleukin-2 production Source: UniProtKB
  • negative regulation of interleukin-3 production Source: MGI
  • negative regulation of interleukin-6 production Source: UniProtKB
  • negative regulation of myeloid dendritic cell activation Source: MGI
  • negative regulation of natural killer cell activation Source: UniProtKB
  • negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target Source: UniProtKB
  • negative regulation of NF-kappaB transcription factor activity Source: MGI
  • negative regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell Source: MGI
  • negative regulation of T cell proliferation Source: UniProtKB
  • negative regulation of T-helper 1 type immune response Source: UniProtKB
  • negative regulation of tumor necrosis factor production Source: MGI
  • negative regulation of type I interferon production Source: UniProtKB
  • positive regulation of chemokine production Source: UniProtKB
  • positive regulation of cytokine production Source: UniProtKB
  • positive regulation of defense response to bacterium Source: UniProtKB
  • positive regulation of ERK1 and ERK2 cascade Source: UniProtKB
  • positive regulation of innate immune response Source: UniProtKB
  • positive regulation of interferon-gamma production Source: UniProtKB
  • positive regulation of interleukin-1 production Source: UniProtKB
  • positive regulation of interleukin-4 production Source: MGI
  • positive regulation of macrophage activation Source: UniProtKB
  • positive regulation of NIK/NF-kappaB signaling Source: UniProtKB
  • positive regulation of T cell proliferation Source: UniProtKB
  • positive regulation of tumor necrosis factor secretion Source: UniProtKB
  • regulation of tolerance induction dependent upon immune response Source: UniProtKB
  • toll-like receptor 3 signaling pathway Source: UniProtKB
  • toll-like receptor 7 signaling pathway Source: UniProtKB
  • toll-like receptor 9 signaling pathway Source: UniProtKB


Biological processAdaptive immunity, Immunity, Inflammatory response, Innate immunity

Enzyme and pathway databases

ReactomeiR-MMU-451927. Interleukin-2 signaling.

Names & Taxonomyi

Protein namesi
Recommended name:
Hepatitis A virus cellular receptor 2 homolog
Short name:
Alternative name(s):
T-cell immunoglobulin and mucin domain-containing protein 3
Short name:
T-cell immunoglobulin mucin receptor 3
Short name:
T-cell membrane protein 3
Gene namesi
Synonyms:Tim3, Timd3
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
  • UP000000589 Componenti: Chromosome 11

Organism-specific databases

MGIiMGI:2159682. Havcr2.

Subcellular locationi

Isoform 1 :
  • Membrane Curated; Single-pass type I membrane protein Curated
  • Cell junction By similarity

  • Note: Localizes to the immunological synapse between CD8+ T-cells and target cells.By similarity
Isoform 2 :


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini20 – 193ExtracellularSequence analysisAdd BLAST174
Transmembranei194 – 214HelicalSequence analysisAdd BLAST21
Topological domaini215 – 281CytoplasmicSequence analysisAdd BLAST67

GO - Cellular componenti

  • cell junction Source: UniProtKB-SubCell
  • cell surface Source: UniProtKB
  • early endosome Source: UniProtKB
  • extracellular exosome Source: MGI
  • immunological synapse Source: UniProtKB
  • integral component of membrane Source: UniProtKB-KW
  • plasma membrane Source: Reactome

Keywords - Cellular componenti

Cell junction, Membrane, Secreted

Pathology & Biotechi


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi53W → A: Greatly decreases phosphatidylserine binding. 1 Publication1
Mutagenesisi60 – 62WSQ → VFE: Decreases phosphatidylserine binding. 1 Publication3
Mutagenesisi62Q → A: No effect on phagocytic activity. 1 Publication1
Mutagenesisi112R → A: Abolishes phagocytic activity. 1 Publication1
Mutagenesisi118 – 119LM → AA: Decreases phosphatidylserine binding. 1 Publication2
Mutagenesisi120 – 121ND → AA: Decreases phosphatidylserine binding, abolishes phagocytic activity. 2 Publications2
Mutagenesisi256Y → F: Abolishes phosphorylation, disrupts interaction with PIK3R1 and PIK3R2, no LGALS9-mediated disruption of interaction with BAG6; when associated with F-263. 2 Publications1
Mutagenesisi263Y → F: Abolishes phosphorylation, disrupts interaction with PIK3R1 and PIK3R2, no LGALS9-mediated disruption of interaction with BAG6; when associated with F-256. 2 Publications1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 19Sequence analysisAdd BLAST19
ChainiPRO_000004210220 – 281Hepatitis A virus cellular receptor 2 homologAdd BLAST262

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi38 ↔ 111PROSITE-ProRule annotationCombined sources1 Publication
Disulfide bondi52 ↔ 63PROSITE-ProRule annotationCombined sources1 Publication
Disulfide bondi58 ↔ 110PROSITE-ProRule annotationCombined sources1 Publication
Glycosylationi74N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi100N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi146O-linked (GalNAc...) threonineBy similarity1
Glycosylationi172N-linked (GlcNAc...) asparagineSequence analysis1
Modified residuei256Phosphotyrosine; by ITKBy similarity1

Post-translational modificationi

Phosphorylated on tyrosine residues; modestly increased after TCR/CD28 stimulation. Can be phosphorylated in the cytoplasmatic domain by FYN (PubMed:21807895). Phosphorylation at Tyr-256 is increased by stimulation with ligand LGALS9 (By similarity).By similarity1 Publication
N-glycosylated.1 Publication

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases


PTM databases



Tissue specificityi

Expressed in T-helper type 1 lymphocytes. Not expressed by naive T-cells but up-regulated as they differentiate into T-helper-1 cells. Also expressed by differentiated type 1 CD8+ cytotoxic T-cells. Expressed on peritoneal exudate macrophages, monocytes, and splenic dendritic cells (DCs). Expression on natural killer (NK) cells is inversely associated with IFN-gamma production during the initial 24 h of LPS-induced endotoxic shock. Expressed on mast cells.6 Publications

Gene expression databases

ExpressionAtlasiQ8VIM0. baseline and differential.
GenevisibleiQ8VIM0. MM.


Subunit structurei

Interacts with HMGB1; impairs HMGB1 binding to B-DNA and likely HMGB1-mediated innate immume response (PubMed:22842346). Interacts with BAG6 (PubMed:22863785). Interacts (phosphorylated) with PIK3R1 and PIK3R2. Interacts (not dependent on its phosphorylation status) with FYN (PubMed:21807895). 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 (By similarity).By similarity3 Publications

Binary interactionsi

Show more details

Protein-protein interaction databases

BioGridi228588. 1 interactor.
IntActiQ8VIM0. 6 interactors.


Secondary structure

Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi34 – 36Combined sources3
Beta strandi51 – 57Combined sources7
Beta strandi60 – 62Combined sources3
Beta strandi66 – 70Combined sources5
Beta strandi72 – 77Combined sources6
Beta strandi81 – 85Combined sources5
Helixi89 – 91Combined sources3
Beta strandi96 – 100Combined sources5
Helixi103 – 105Combined sources3
Beta strandi107 – 113Combined sources7
Beta strandi116 – 119Combined sources4
Beta strandi125 – 130Combined sources6

3D structure databases

Select the link destinations:
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum

Miscellaneous databases


Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini20 – 125Ig-like V-typeAdd BLAST106


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni252 – 270Interaction with BAG61 PublicationAdd BLAST19

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi221 – 224Poly-Lys4


The Ig-like V-type (immunoglobulin-like) domain mediates binding to PtSer involving a Ca2+ ion.1 Publication

Sequence similaritiesi

Belongs to the immunoglobulin superfamily. TIM family.Curated

Keywords - Domaini

Immunoglobulin domain, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410IJGA. Eukaryota.

Family and domain databases

Gene3Di2.60.40.10. 1 hit.
InterProiView protein in InterPro
IPR007110. Ig-like_dom.
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: Q8VIM0-1) [UniParc]FASTAAdd to basket
Also known as: Tim-3L, flTim-3

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.

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60 70 80 90 100
110 120 130 140 150
160 170 180 190 200
210 220 230 240 250
260 270 280
Mass (Da):30,934
Last modified:March 1, 2002 - v1
Isoform 2 (identifier: Q8VIM0-2) [UniParc]FASTAAdd to basket
Also known as: sTim-3

The sequence of this isoform differs from the canonical sequence as follows:

Show »
Mass (Da):22,087


Polymorphic differences between BALB/c and HBA alleles in the Ig-like V-type domain are the reason for distinct binding affinities for PtSer. The HBA2 allele binds PtSer approximately 50% less than BALB/c.1 Publication

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_058116133 – 217AKVTP…LILKW → G in isoform 2. 1 PublicationAdd BLAST85

Sequence databases

Select the link destinations:
Links Updated
AF399831 mRNA. Translation: AAL35776.1.
AL669948 Genomic DNA. No translation available.
CCDSiCCDS36135.1. [Q8VIM0-1]
RefSeqiNP_599011.2. NM_134250.2. [Q8VIM0-1]

Genome annotation databases

EnsembliENSMUST00000020668; ENSMUSP00000020668; ENSMUSG00000020399. [Q8VIM0-1]
UCSCiuc011xtp.1. mouse. [Q8VIM0-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

Entry informationi

Entry nameiHAVR2_MOUSE
AccessioniPrimary (citable) accession number: Q8VIM0
Entry historyiIntegrated into UniProtKB/Swiss-Prot: September 27, 2005
Last sequence update: March 1, 2002
Last modified: May 10, 2017
This is version 119 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program



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.Curated

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome


  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  3. SIMILARITY comments
    Index of protein domains and families