TIMD4_MOUSE
ID TIMD4_MOUSE Reviewed; 343 AA.
AC Q6U7R4; Q6U7R3; Q8CIC7;
DT 27-SEP-2005, integrated into UniProtKB/Swiss-Prot.
DT 27-SEP-2005, sequence version 2.
DT 03-AUG-2022, entry version 124.
DE RecName: Full=T-cell immunoglobulin and mucin domain-containing protein 4;
DE Short=TIMD-4;
DE AltName: Full=Spleen, mucin-containing, knockout of lymphotoxin protein;
DE Short=SMUCKLER;
DE AltName: Full=T-cell immunoglobulin mucin receptor 4;
DE Short=TIM-4;
DE AltName: Full=T-cell membrane protein 4;
DE Flags: Precursor;
GN Name=Timd4; Synonyms=Tim4;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], VARIANTS MET-12 AND 209-ILE, FUNCTION,
RP INDUCTION, AND TISSUE SPECIFICITY.
RC STRAIN=BALB/cJ, and C57BL/6J;
RX PubMed=14768054; DOI=10.1002/eji.200324590;
RA Shakhov A.N., Rybtsov S., Tumanov A.V., Shulenin S., Dean M., Kuprash D.V.,
RA Nedospasov S.A.;
RT "SMUCKLER/TIM4 is a distinct member of TIM family expressed by stromal
RT cells of secondary lymphoid tissues and associated with lymphotoxin
RT signaling.";
RL Eur. J. Immunol. 34:494-503(2004).
RN [2]
RP FUNCTION, AND INTERACTION WITH HAVCR1/TIM1.
RX PubMed=15793576; DOI=10.1038/ni1185;
RA Meyers J.H., Chakravarti S., Schlesinger D., Illes Z., Waldner H.,
RA Umetsu S.E., Kenny J., Zheng X.X., Umetsu D.T., DeKruyff R.H., Strom T.B.,
RA Kuchroo V.K.;
RT "TIM-4 is the ligand for TIM-1, and the TIM-1-TIM-4 interaction regulates T
RT cell proliferation.";
RL Nat. Immunol. 6:455-464(2005).
RN [3]
RP FUNCTION, TISSUE SPECIFICITY, AND SUBUNIT.
RX PubMed=17960135; DOI=10.1038/nature06307;
RA Miyanishi M., Tada K., Koike M., Uchiyama Y., Kitamura T., Nagata S.;
RT "Identification of Tim4 as a phosphatidylserine receptor.";
RL Nature 450:435-439(2007).
RN [4]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=18354194; DOI=10.4049/jimmunol.180.7.4706;
RA Rodriguez-Manzanet R., Meyers J.H., Balasubramanian S., Slavik J.,
RA Kassam N., Dardalhon V., Greenfield E.A., Anderson A.C., Sobel R.A.,
RA Hafler D.A., Strom T.B., Kuchroo V.K.;
RT "TIM-4 expressed on APCs induces T cell expansion and survival.";
RL J. Immunol. 180:4706-4713(2008).
RN [5]
RP FUNCTION.
RX PubMed=18367551; DOI=10.1093/intimm/dxn029;
RA Mizui M., Shikina T., Arase H., Suzuki K., Yasui T., Rennert P.D.,
RA Kumanogoh A., Kikutani H.;
RT "Bimodal regulation of T cell-mediated immune responses by TIM-4.";
RL Int. Immunol. 20:695-708(2008).
RN [6]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=31263038; DOI=10.4049/jimmunol.1900117;
RA Liu W., Bai F., Wang H., Liang Y., Du X., Liu C., Cai D., Peng J.,
RA Zhong G., Liang X., Ma C., Gao L.;
RT "Tim-4 Inhibits NLRP3 Inflammasome via the LKB1/AMPKalpha Pathway in
RT Macrophages.";
RL J. Immunol. 203:990-1000(2019).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-323; SER-325 AND SER-331, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 25-134 IN COMPLEX WITH
RP PHOSPHATIDYLSERINE, AND DISULFIDE BONDS.
RX PubMed=18083575; DOI=10.1016/j.immuni.2007.11.008;
RA Santiago C., Ballesteros A., Martinez-Munoz L., Mellado M., Kaplan G.G.,
RA Freeman G.J., Casasnovas J.M.;
RT "Structures of T cell immunoglobulin mucin protein 4 show a metal-ion-
RT dependent ligand binding site where phosphatidylserine binds.";
RL Immunity 27:941-951(2007).
CC -!- FUNCTION: Phosphatidylserine receptor that plays different role in
CC immune response including phagocytosis of apoptotic cells and T-cell
CC regulation (PubMed:17960135). Controls T-cell activation in a bimodal
CC fashion, decreasing the activation of naive T-cells by inducing cell
CC cycle arrest, while increasing proliferation of activated T-cells by
CC activating AKT1 and ERK1/2 phosphorylations and subsequent signaling
CC pathways. Also plays a role in efferocytosis which is the process by
CC which apoptotic cells are removed by phagocytic cells (PubMed:18354194,
CC PubMed:18367551). Mechanistically, promotes the engulfment of apoptotic
CC cells or exogenous particles by securing them to phagocytes through
CC direct binding to phosphatidylserine present on apoptotic cells, while
CC other engulfment receptors such as MERTK efficiently recognize
CC apoptotic cells and mediate their ingestion (By similarity).
CC Additionally, promotes autophagy process by suppressing NLRP3
CC inflammasome activity via activation of STK11/PRKAA1 pathway in a
CC phosphatidylserine-dependent mechanism (PubMed:31263038).
CC {ECO:0000250|UniProtKB:Q96H15, ECO:0000269|PubMed:17960135,
CC ECO:0000269|PubMed:18354194, ECO:0000269|PubMed:18367551,
CC ECO:0000269|PubMed:31263038}.
CC -!- SUBUNIT: Homodimer. {ECO:0000305|PubMed:17960135,
CC ECO:0000305|PubMed:18083575}.
CC -!- INTERACTION:
CC Q6U7R4; Q5QNS5: Havcr1; NbExp=4; IntAct=EBI-16764486, EBI-20217708;
CC Q6U7R4; Q5QNS5-2: Havcr1; NbExp=2; IntAct=EBI-16764486, EBI-20217763;
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305}; Single-pass type I
CC membrane protein {ECO:0000305}.
CC -!- TISSUE SPECIFICITY: Predominantly expressed in lymphoid tissues, such
CC as spleen, lymph nodes, and Peyer patches. Also expressed in fetal
CC liver, salivary gland, and spleen stromal cells, predominantly in the
CC marginal zone and to a lesser extent throughout the white pulp. Not
CC expressed in bone marrow-derived cells. Expressed mainly by antigen
CC presenting cells (APCs) in T- and B-cell areas, but not by T- or B-
CC lymphocytes. {ECO:0000269|PubMed:14768054, ECO:0000269|PubMed:17960135,
CC ECO:0000269|PubMed:18354194}.
CC -!- INDUCTION: Down-regulated in lymphotoxin deficient mice.
CC {ECO:0000269|PubMed:14768054}.
CC -!- DISRUPTION PHENOTYPE: Deletion mice maintained on methionine and
CC choline-deficient diet exhibit significantly more obvious inflammation
CC and severe lipid accumulation. {ECO:0000269|PubMed:31263038}.
CC -!- MISCELLANEOUS: Belongs to the T-cell and airway phenotype regulator
CC (Tapr) locus, a single chromosomal region that confers reduced T-helper
CC type 2 responsiveness and protects against airway hyperactivity (AHR),
CC the hallmark of human asthma.
CC -!- MISCELLANEOUS: Low expression of Timd4 is associated with lymphotoxin
CC deficiency.
CC -!- SIMILARITY: Belongs to the immunoglobulin superfamily. TIM family.
CC {ECO:0000305}.
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DR EMBL; AY376717; AAR23484.1; -; mRNA.
DR EMBL; AY376716; AAR23483.1; -; mRNA.
DR CCDS; CCDS36137.1; -.
DR RefSeq; NP_848874.3; NM_178759.4.
DR PDB; 3BI9; X-ray; 2.95 A; X=24-134.
DR PDB; 3BIA; X-ray; 2.20 A; X=24-134.
DR PDB; 3BIB; X-ray; 2.50 A; X=24-134.
DR PDBsum; 3BI9; -.
DR PDBsum; 3BIA; -.
DR PDBsum; 3BIB; -.
DR AlphaFoldDB; Q6U7R4; -.
DR SMR; Q6U7R4; -.
DR IntAct; Q6U7R4; 1.
DR STRING; 10090.ENSMUSP00000069456; -.
DR GlyGen; Q6U7R4; 1 site.
DR iPTMnet; Q6U7R4; -.
DR PhosphoSitePlus; Q6U7R4; -.
DR SwissPalm; Q6U7R4; -.
DR MaxQB; Q6U7R4; -.
DR PaxDb; Q6U7R4; -.
DR PeptideAtlas; Q6U7R4; -.
DR PRIDE; Q6U7R4; -.
DR ProteomicsDB; 259394; -.
DR ABCD; Q6U7R4; 10 sequenced antibodies.
DR Antibodypedia; 2737; 454 antibodies from 37 providers.
DR DNASU; 276891; -.
DR Ensembl; ENSMUST00000068877; ENSMUSP00000069456; ENSMUSG00000055546.
DR GeneID; 276891; -.
DR KEGG; mmu:276891; -.
DR UCSC; uc007iox.1; mouse.
DR CTD; 91937; -.
DR MGI; MGI:2445125; Timd4.
DR VEuPathDB; HostDB:ENSMUSG00000055546; -.
DR eggNOG; ENOG502S1A2; Eukaryota.
DR GeneTree; ENSGT00940000161609; -.
DR HOGENOM; CLU_047504_0_1_1; -.
DR InParanoid; Q6U7R4; -.
DR OMA; QSRNSMC; -.
DR OrthoDB; 1147868at2759; -.
DR PhylomeDB; Q6U7R4; -.
DR TreeFam; TF336163; -.
DR BioGRID-ORCS; 276891; 5 hits in 74 CRISPR screens.
DR EvolutionaryTrace; Q6U7R4; -.
DR PRO; PR:Q6U7R4; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; Q6U7R4; protein.
DR Bgee; ENSMUSG00000055546; Expressed in peripheral lymph node and 45 other tissues.
DR Genevisible; Q6U7R4; MM.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0001786; F:phosphatidylserine binding; IDA:MGI.
DR GO; GO:0043277; P:apoptotic cell clearance; IDA:MGI.
DR GO; GO:0060097; P:cytoskeletal rearrangement involved in phagocytosis, engulfment; IBA:GO_Central.
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 1: Evidence at protein level;
KW 3D-structure; Disulfide bond; Glycoprotein; Immunoglobulin domain;
KW Membrane; Phosphoprotein; Reference proteome; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1..22
FT /evidence="ECO:0000255"
FT CHAIN 23..343
FT /note="T-cell immunoglobulin and mucin domain-containing
FT protein 4"
FT /id="PRO_0000042104"
FT TOPO_DOM 23..279
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 280..300
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 301..343
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 23..128
FT /note="Ig-like V-type"
FT REGION 239..258
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 313..343
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 314..343
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 323
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 325
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 331
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT CARBOHYD 220
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 40..112
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114,
FT ECO:0000269|PubMed:18083575"
FT DISULFID 53..64
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114,
FT ECO:0000269|PubMed:18083575"
FT DISULFID 59..111
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114,
FT ECO:0000269|PubMed:18083575"
FT VARIANT 12
FT /note="T -> M (in strain: C57BL/6)"
FT /evidence="ECO:0000269|PubMed:14768054"
FT VARIANT 209
FT /note="F -> I (in strain: C57BL/6)"
FT STRAND 26..31
FT /evidence="ECO:0007829|PDB:3BIA"
FT STRAND 36..38
FT /evidence="ECO:0007829|PDB:3BIA"
FT TURN 47..49
FT /evidence="ECO:0007829|PDB:3BIA"
FT STRAND 51..58
FT /evidence="ECO:0007829|PDB:3BIA"
FT STRAND 61..63
FT /evidence="ECO:0007829|PDB:3BIA"
FT STRAND 67..71
FT /evidence="ECO:0007829|PDB:3BIA"
FT STRAND 73..81
FT /evidence="ECO:0007829|PDB:3BIA"
FT STRAND 84..86
FT /evidence="ECO:0007829|PDB:3BIA"
FT HELIX 90..92
FT /evidence="ECO:0007829|PDB:3BIA"
FT STRAND 97..99
FT /evidence="ECO:0007829|PDB:3BIA"
FT HELIX 104..106
FT /evidence="ECO:0007829|PDB:3BIA"
FT STRAND 108..115
FT /evidence="ECO:0007829|PDB:3BIA"
FT STRAND 117..120
FT /evidence="ECO:0007829|PDB:3BIA"
FT STRAND 123..132
FT /evidence="ECO:0007829|PDB:3BIA"
SQ SEQUENCE 343 AA; 37548 MW; D2D5539A7CDB8290 CRC64;
MSKGLLLLWL VTELWWLYLT PAASEDTIIG FLGQPVTLPC HYLSWSQSRN SMCWGKGSCP
NSKCNAELLR TDGTRIISRK STKYTLLGKV QFGEVSLTIS NTNRGDSGVY CCRIEVPGWF
NDVKKNVRLE LRRATTTKKP TTTTRPTTTP YVTTTTPELL PTTVMTTSVL PTTTPPQTLA
TTAFSTAVTT CPSTTPGSFS QETTKGSAFT TESETLPASN HSQRSMMTIS TDIAVLRPTG
SNPGILPSTS QLTTQKTTLT TSESLQKTTK SHQINSRQTI LIIACCVGFV LMVLLFLAFL
LRGKVTGANC LQRHKRPDNT EDSDSVLNDM SHGRDDEDGI FTL
