HAVR2_RAT
ID HAVR2_RAT Reviewed; 282 AA.
AC P0C0K5; G3V9I4;
DT 27-SEP-2005, integrated into UniProtKB/Swiss-Prot.
DT 17-FEB-2016, sequence version 2.
DT 03-AUG-2022, entry version 98.
DE RecName: Full=Hepatitis A virus cellular receptor 2 homolog;
DE Short=HAVcr-2;
DE AltName: Full=T-cell immunoglobulin and mucin domain-containing protein 3;
DE Short=TIMD-3;
DE AltName: Full=T-cell immunoglobulin mucin receptor 3;
DE Short=TIM-3;
DE AltName: Full=T-cell membrane protein 3;
DE AltName: CD_antigen=CD366;
DE Flags: Precursor;
GN Name=Havcr2; Synonyms=Tim3, Timd3;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RX PubMed=15057822; DOI=10.1038/nature02426;
RA Gibbs R.A., Weinstock G.M., Metzker M.L., Muzny D.M., Sodergren E.J.,
RA Scherer S., Scott G., Steffen D., Worley K.C., Burch P.E., Okwuonu G.,
RA Hines S., Lewis L., Deramo C., Delgado O., Dugan-Rocha S., Miner G.,
RA Morgan M., Hawes A., Gill R., Holt R.A., Adams M.D., Amanatides P.G.,
RA Baden-Tillson H., Barnstead M., Chin S., Evans C.A., Ferriera S.,
RA Fosler C., Glodek A., Gu Z., Jennings D., Kraft C.L., Nguyen T.,
RA Pfannkoch C.M., Sitter C., Sutton G.G., Venter J.C., Woodage T., Smith D.,
RA Lee H.-M., Gustafson E., Cahill P., Kana A., Doucette-Stamm L.,
RA Weinstock K., Fechtel K., Weiss R.B., Dunn D.M., Green E.D.,
RA Blakesley R.W., Bouffard G.G., De Jong P.J., Osoegawa K., Zhu B., Marra M.,
RA Schein J., Bosdet I., Fjell C., Jones S., Krzywinski M., Mathewson C.,
RA Siddiqui A., Wye N., McPherson J., Zhao S., Fraser C.M., Shetty J.,
RA Shatsman S., Geer K., Chen Y., Abramzon S., Nierman W.C., Havlak P.H.,
RA Chen R., Durbin K.J., Egan A., Ren Y., Song X.-Z., Li B., Liu Y., Qin X.,
RA Cawley S., Cooney A.J., D'Souza L.M., Martin K., Wu J.Q.,
RA Gonzalez-Garay M.L., Jackson A.R., Kalafus K.J., McLeod M.P.,
RA Milosavljevic A., Virk D., Volkov A., Wheeler D.A., Zhang Z., Bailey J.A.,
RA Eichler E.E., Tuzun E., Birney E., Mongin E., Ureta-Vidal A., Woodwark C.,
RA Zdobnov E., Bork P., Suyama M., Torrents D., Alexandersson M., Trask B.J.,
RA Young J.M., Huang H., Wang H., Xing H., Daniels S., Gietzen D., Schmidt J.,
RA Stevens K., Vitt U., Wingrove J., Camara F., Mar Alba M., Abril J.F.,
RA Guigo R., Smit A., Dubchak I., Rubin E.M., Couronne O., Poliakov A.,
RA Huebner N., Ganten D., Goesele C., Hummel O., Kreitler T., Lee Y.-A.,
RA Monti J., Schulz H., Zimdahl H., Himmelbauer H., Lehrach H., Jacob H.J.,
RA Bromberg S., Gullings-Handley J., Jensen-Seaman M.I., Kwitek A.E.,
RA Lazar J., Pasko D., Tonellato P.J., Twigger S., Ponting C.P., Duarte J.M.,
RA Rice S., Goodstadt L., Beatson S.A., Emes R.D., Winter E.E., Webber C.,
RA Brandt P., Nyakatura G., Adetobi M., Chiaromonte F., Elnitski L.,
RA Eswara P., Hardison R.C., Hou M., Kolbe D., Makova K., Miller W.,
RA Nekrutenko A., Riemer C., Schwartz S., Taylor J., Yang S., Zhang Y.,
RA Lindpaintner K., Andrews T.D., Caccamo M., Clamp M., Clarke L., Curwen V.,
RA Durbin R.M., Eyras E., Searle S.M., Cooper G.M., Batzoglou S., Brudno M.,
RA Sidow A., Stone E.A., Payseur B.A., Bourque G., Lopez-Otin C., Puente X.S.,
RA Chakrabarti K., Chatterji S., Dewey C., Pachter L., Bray N., Yap V.B.,
RA Caspi A., Tesler G., Pevzner P.A., Haussler D., Roskin K.M., Baertsch R.,
RA Clawson H., Furey T.S., Hinrichs A.S., Karolchik D., Kent W.J.,
RA Rosenbloom K.R., Trumbower H., Weirauch M., Cooper D.N., Stenson P.D.,
RA Ma B., Brent M., Arumugam M., Shteynberg D., Copley R.R., Taylor M.S.,
RA Riethman H., Mudunuri U., Peterson J., Guyer M., Felsenfeld A., Old S.,
RA Mockrin S., Collins F.S.;
RT "Genome sequence of the Brown Norway rat yields insights into mammalian
RT evolution.";
RL Nature 428:493-521(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 22-185.
RC STRAIN=Lewis.1AV1; TISSUE=Spleen;
RX PubMed=15020066; DOI=10.1016/j.jneuroim.2003.12.012;
RA Wefer J., Harris R.A., Lobell A.;
RT "Protective DNA vaccination against experimental autoimmune
RT encephalomyelitis is associated with induction of IFNbeta.";
RL J. Neuroimmunol. 149:66-76(2004).
RN [4]
RP TISSUE SPECIFICITY DURING EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS.
RX PubMed=15913792; DOI=10.1016/j.jneuroim.2005.04.004;
RA Gielen A.W., Lobell A., Lidman O., Khademi M., Olsson T., Piehl F.;
RT "Expression of T cell immunoglobulin- and mucin-domain-containing
RT molecules-1 and -3 (TIM-1 and -3) in the rat nervous and immune systems.";
RL J. Neuroimmunol. 164:93-104(2005).
CC -!- FUNCTION: Cell surface receptor implicated in modulating innate and
CC adaptive immune responses. Generally accepted to have an inhibiting
CC function. Reports on stimulating functions suggest that the activity
CC may be influenced by the cellular context and/or the respective ligand.
CC Regulates macrophage activation. Inhibits T-helper type 1 lymphocyte
CC (Th1)-mediated auto- and alloimmune responses and promotes
CC immunological tolerance. In CD8+ cells attenuates TCR-induced
CC signaling, specifically by blocking NF-kappaB and NFAT promoter
CC activities resulting in the loss of IL-2 secretion. The function may
CC implicate its association with LCK proposed to impair phosphorylation
CC of TCR subunits. In contrast, shown to activate TCR-induced signaling
CC in T-cells probably implicating ZAP70, LCP2, LCK and FYN. Expressed on
CC Treg cells can inhibit Th17 cell responses. Receptor for LGALS9.
CC Binding to LGALS9 is believed to result in suppression of T-cell
CC responses; the resulting apoptosis of antigen-specific cells may
CC implicate HAVCR2 phosphorylation and disruption of its association with
CC BAG6. Binding to LGALS9 is proposed to be involved in innate immune
CC response to intracellular pathogens. Expressed on Th1 cells interacts
CC with LGALS9 expressed on Mycobacterium tuberculosis-infected
CC macrophages to stimulate antibactericidal activity including IL-1 beta
CC secretion and to restrict intracellular bacterial growth. However, the
CC function as receptor for LGALS9 has been challenged (By similarity).
CC Also reported to enhance CD8+ T cell responses to an acute infection
CC such as by Listeria monocytogenes. Receptor for phosphatidylserine
CC (PtSer); PtSer-binding is calcium-dependent. May recognize PtSer on
CC apoptotic cells leading to their phagocytosis. Mediates the engulfment
CC of apoptotic cells by dendritic cells. Expressed on T-cells, promotes
CC conjugation but not engulfment of apoptotic cells. Expressed on
CC dendritic cells (DCs) positively regulates innate immune response and
CC in synergy with Toll-like receptors promotes secretion of TNF-alpha. In
CC tumor-imfiltrating DCs suppresses nucleic acid-mediated innate immune
CC repsonse by interaction with HMGB1 and interfering with nucleic acid-
CC sensing and trafficking of nucleid acids to endosomes. Can enhance mast
CC cell production of Th2 cytokines Il-4, IL-6 and IL-13. Expressed on
CC natural killer (NK) cells acts as a coreceptor to enhance IFN-gamma
CC production in response to LGALS9. In contrast, shown to suppress NK
CC cell-mediated cytotoxicity. Negatively regulates NK cell function in
CC LPS-induced endotoxic shock. {ECO:0000250|UniProtKB:Q8TDQ0,
CC ECO:0000250|UniProtKB:Q8VIM0}.
CC -!- SUBUNIT: Interacts with HMGB1; impairs HMGB1 binding to B-DNA and
CC likely HMGB1-mediated innate immune response. Interacts with BAG6.
CC Interacts (phosphorylated) with PIK3R1 and PIK3R2. Interacts (not
CC dependent on its phosphorylation status) with FYN. Interacts (in basal
CC state T-cells) with VAV1; AKT1/2, LCP2, ZAP70, SYK, PIK3R1, FYN, SH3BP2
CC and SH2D2A. Interacts (in activated T-cells) with LCK and PLCG.
CC Interacts with ILF3; this interaction promotes ILF3 ubiquitination and
CC degradation. {ECO:0000250|UniProtKB:Q8TDQ0,
CC ECO:0000250|UniProtKB:Q8VIM0}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305}; Single-pass type I
CC membrane protein {ECO:0000305}. Cell junction
CC {ECO:0000250|UniProtKB:Q8TDQ0}. Note=Localizes to the immunological
CC synapse between CD8+ T-cells and target cells.
CC {ECO:0000250|UniProtKB:Q8TDQ0}.
CC -!- MISCELLANEOUS: Expression is up-regulated in the spinal cord during
CC experimental autoimmune encephalomyelitis (EAE) and following antigen
CC restimulation of the encephalitogenic TCRBV8S2+ population. Expression
CC was also detected by in situ hybridization in resident cells of the
CC nervous system.
CC -!- SIMILARITY: Belongs to the immunoglobulin superfamily. TIM family.
CC {ECO:0000305}.
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DR EMBL; CH473948; EDM04175.1; -; Genomic_DNA.
DR EMBL; AABR07029515; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AJ549521; CAD79372.1; -; mRNA.
DR RefSeq; NP_001094232.1; NM_001100762.1.
DR AlphaFoldDB; P0C0K5; -.
DR STRING; 10116.ENSRNOP00000048351; -.
DR GlyGen; P0C0K5; 4 sites.
DR PaxDb; P0C0K5; -.
DR Ensembl; ENSRNOT00000048485; ENSRNOP00000048351; ENSRNOG00000031443.
DR GeneID; 363578; -.
DR KEGG; rno:363578; -.
DR UCSC; RGD:1305233; rat.
DR CTD; 84868; -.
DR RGD; 1305233; Havcr2.
DR eggNOG; ENOG502S454; Eukaryota.
DR GeneTree; ENSGT00940000154444; -.
DR InParanoid; P0C0K5; -.
DR OMA; EHGPAET; -.
DR OrthoDB; 1147868at2759; -.
DR TreeFam; TF336163; -.
DR PRO; PR:P0C0K5; -.
DR Proteomes; UP000002494; Chromosome 10.
DR Proteomes; UP000234681; Chromosome 10.
DR Bgee; ENSRNOG00000031443; Expressed in duodenum and 10 other tissues.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-SubCell.
DR GO; GO:0009986; C:cell surface; IDA:RGD.
DR GO; GO:0005769; C:early endosome; ISO:RGD.
DR GO; GO:0001772; C:immunological synapse; ISO:RGD.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0002250; P:adaptive immune response; IEA:UniProtKB-KW.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; ISO:RGD.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; ISO:RGD.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0002281; P:macrophage activation involved in immune response; ISO:RGD.
DR GO; GO:0060135; P:maternal process involved in female pregnancy; ISO:RGD.
DR GO; GO:0002519; P:natural killer cell tolerance induction; ISO:RGD.
DR GO; GO:1900425; P:negative regulation of defense response to bacterium; ISO:RGD.
DR GO; GO:0010629; P:negative regulation of gene expression; ISO:RGD.
DR GO; GO:0071656; P:negative regulation of granulocyte colony-stimulating factor production; ISO:RGD.
DR GO; GO:0002838; P:negative regulation of immune response to tumor cell; ISO:RGD.
DR GO; GO:2000521; P:negative regulation of immunological synapse formation; ISO:RGD.
DR GO; GO:0045824; P:negative regulation of innate immune response; ISO:RGD.
DR GO; GO:0032687; P:negative regulation of interferon-alpha production; ISO:RGD.
DR GO; GO:0032689; P:negative regulation of interferon-gamma production; ISO:RGD.
DR GO; GO:0032703; P:negative regulation of interleukin-2 production; ISO:RGD.
DR GO; GO:0032712; P:negative regulation of interleukin-3 production; ISO:RGD.
DR GO; GO:0032715; P:negative regulation of interleukin-6 production; ISO:RGD.
DR GO; GO:0030886; P:negative regulation of myeloid dendritic cell activation; ISO:RGD.
DR GO; GO:0032815; P:negative regulation of natural killer cell activation; ISO:RGD.
DR GO; GO:0002859; P:negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target; ISO:RGD.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; ISO:RGD.
DR GO; GO:2001189; P:negative regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell; ISO:RGD.
DR GO; GO:0042130; P:negative regulation of T cell proliferation; ISO:RGD.
DR GO; GO:0002826; P:negative regulation of T-helper 1 type immune response; ISO:RGD.
DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; ISO:RGD.
DR GO; GO:0032480; P:negative regulation of type I interferon production; ISO:RGD.
DR GO; GO:0032722; P:positive regulation of chemokine production; ISO:RGD.
DR GO; GO:0001819; P:positive regulation of cytokine production; ISO:RGD.
DR GO; GO:1900426; P:positive regulation of defense response to bacterium; ISO:RGD.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISO:RGD.
DR GO; GO:0045089; P:positive regulation of innate immune response; ISO:RGD.
DR GO; GO:0032729; P:positive regulation of interferon-gamma production; ISO:RGD.
DR GO; GO:0032732; P:positive regulation of interleukin-1 production; ISO:RGD.
DR GO; GO:0032753; P:positive regulation of interleukin-4 production; ISO:RGD.
DR GO; GO:0043032; P:positive regulation of macrophage activation; ISO:RGD.
DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; ISO:RGD.
DR GO; GO:0042102; P:positive regulation of T cell proliferation; ISO:RGD.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISO:RGD.
DR GO; GO:0002652; P:regulation of tolerance induction dependent upon immune response; ISO:RGD.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; ISO:RGD.
DR GO; GO:0034154; P:toll-like receptor 7 signaling pathway; ISO:RGD.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; ISO:RGD.
DR Gene3D; 2.60.40.10; -; 1.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR036179; Ig-like_dom_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR003599; Ig_sub.
DR InterPro; IPR013106; Ig_V-set.
DR Pfam; PF07686; V-set; 1.
DR SMART; SM00409; IG; 1.
DR SUPFAM; SSF48726; SSF48726; 1.
DR PROSITE; PS50835; IG_LIKE; 1.
PE 2: Evidence at transcript level;
KW Adaptive immunity; Cell junction; Disulfide bond; Glycoprotein; Immunity;
KW Immunoglobulin domain; Inflammatory response; Innate immunity; Membrane;
KW Metal-binding; Phosphoprotein; Reference proteome; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT CHAIN 22..282
FT /note="Hepatitis A virus cellular receptor 2 homolog"
FT /id="PRO_0000072703"
FT TOPO_DOM 22..194
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 195..215
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 216..282
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 22..131
FT /note="Ig-like V-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT REGION 138..163
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 253..271
FT /note="Interaction with BAG6"
FT /evidence="ECO:0000250|UniProtKB:Q8VIM0"
FT COMPBIAS 143..163
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 62
FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-L-serine"
FT /ligand_id="ChEBI:CHEBI:57262"
FT /evidence="ECO:0000250|UniProtKB:Q8VIM0"
FT BINDING 112
FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-L-serine"
FT /ligand_id="ChEBI:CHEBI:57262"
FT /evidence="ECO:0000250|UniProtKB:Q8VIM0"
FT BINDING 115
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:Q8VIM0"
FT BINDING 117
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:Q8VIM0"
FT BINDING 119
FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-L-serine"
FT /ligand_id="ChEBI:CHEBI:57262"
FT /evidence="ECO:0000250|UniProtKB:Q8VIM0"
FT BINDING 120
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:Q8VIM0"
FT MOD_RES 257
FT /note="Phosphotyrosine; by ITK"
FT /evidence="ECO:0000250|UniProtKB:Q8TDQ0"
FT CARBOHYD 74
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 100
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 147
FT /note="O-linked (GalNAc...) threonine"
FT /evidence="ECO:0000250|UniProtKB:Q8TDQ0"
FT CARBOHYD 173
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 38..111
FT /evidence="ECO:0000250|UniProtKB:Q8VIM0,
FT ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 52..63
FT /evidence="ECO:0000250|UniProtKB:Q8VIM0,
FT ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 58..110
FT /evidence="ECO:0000250|UniProtKB:Q8VIM0,
FT ECO:0000255|PROSITE-ProRule:PRU00114"
SQ SEQUENCE 282 AA; 30641 MW; 41A5D7F6B0DE96A8 CRC64;
MFSWLPFSCA LLLLQPLPAR SLENAYTAEV GKNAYLPCSY TVPAPGTLVP ICWGKGSCPL
LQCASVVLRT DETNVTYRKS RRYQLKGNFY KGDMSLTIKN VTLADSGTYC CRIQFPGPMN
DEKLELKLSI TEPAKVIPAG TAHGDSTTAS PRTLTTEGSG SETQTLVTLH DNNGTKISTW
ADEIKDSGET IRTAVHIGVG VSAGLALALI LGVLILKWYS SKKKKLQDLS LITLANSPPG
GLVNAGAGRI RSEENIYTIE ENIYEMENSN EYYCYVSSQQ PS
