TIMD4_HUMAN
ID TIMD4_HUMAN Reviewed; 378 AA.
AC Q96H15; B5MCL9;
DT 27-SEP-2005, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 2.
DT 03-AUG-2022, entry version 144.
DE RecName: Full=T-cell immunoglobulin and mucin domain-containing protein 4;
DE Short=TIMD-4;
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 Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT ALA-240.
RC TISSUE=Synovium;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A.,
RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R.,
RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L.,
RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N.,
RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J.,
RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A.,
RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ALA-240.
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP FUNCTION (MICROBIAL INFECTION), AND SUBCELLULAR LOCATION.
RX PubMed=28740388; DOI=10.2147/ijn.s132762;
RA Sims B., Farrow A.L., Williams S.D., Bansal A., Krendelchtchikov A., Gu L.,
RA Matthews Q.L.;
RT "Role of TIM-4 in exosome-dependent entry of HIV-1 into human immune
RT cells.";
RL Int J Nanomedicine 12:4823-4833(2017).
RN [5]
RP FUNCTION, INTERACTION WITH MERKT, AND SUBCELLULAR LOCATION.
RX PubMed=32640697; DOI=10.3390/cells9071625;
RA Moon B., Lee J., Lee S.A., Min C., Moon H., Kim D., Yang S., Moon H.,
RA Jeon J., Joo Y.E., Park D.;
RT "Mertk Interacts with Tim-4 to Enhance Tim-4-Mediated Efferocytosis.";
RL Cells 9:0-0(2020).
RN [6]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=32703939; DOI=10.1038/s41419-020-02773-7;
RA Min C., Park J., Kim G., Moon H., Lee S.A., Kim D., Moon B., Yang S.,
RA Lee J., Kim K., Cho H., Park J., Lee D.H., Lee G., Park D.;
RT "Tim-4 functions as a scavenger receptor for phagocytosis of exogenous
RT particles.";
RL Cell Death Dis. 11:561-561(2020).
RN [7]
RP FUNCTION IN EFFEROCYTOSIS, INTERACTION WITH EPHA2, AND SUBCELLULAR
RP LOCATION.
RX PubMed=34067457; DOI=10.3390/cells10061290;
RA Moon B., Yang S., Kim K., Lee J., Jeong D., Park D.;
RT "EphA2 Interacts with Tim-4 through Association between Its FN3 Domain and
RT the IgV Domain of Tim-4.";
RL Cells 10:0-0(2021).
CC -!- FUNCTION: Phosphatidylserine receptor that plays different role in
CC immune response including phagocytosis of apoptotic cells and T-cell
CC regulation. Controls T-cell activation in a bimodal fashion, decreasing
CC the activation of naive T-cells by inducing cell cycle arrest, while
CC increasing proliferation of activated T-cells by activating AKT1 and
CC ERK1/2 phosphorylations and subsequent signaling pathways (By
CC similarity). Also plays a role in efferocytosis which is the process by
CC which apoptotic cells are removed by phagocytic cells (PubMed:32703939,
CC PubMed:34067457). 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 (PubMed:32640697).
CC Additionally, promotes autophagy process by suppressing NLRP3
CC inflammasome activity via activation of LKB1/PRKAA1 pathway in a
CC phosphatidylserine-dependent mechanism (By similarity).
CC {ECO:0000250|UniProtKB:Q6U7R4, ECO:0000269|PubMed:32640697,
CC ECO:0000269|PubMed:32703939, ECO:0000269|PubMed:34067457}.
CC -!- FUNCTION: (Microbial infection) Plays a positive role in exosome-
CC mediated trafficking of HIV-1 virus and its entry into immune cells.
CC {ECO:0000269|PubMed:28740388}.
CC -!- SUBUNIT: Interacts with MERTK; this interaction enhances TIMD4-mediated
CC efferocytosis (PubMed:32640697). Interacts with EPHA2
CC (PubMed:34067457). {ECO:0000269|PubMed:32640697,
CC ECO:0000269|PubMed:34067457}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:32640697,
CC ECO:0000269|PubMed:32703939, ECO:0000269|PubMed:34067457}; Single-pass
CC type I membrane protein {ECO:0000305}. Secreted, extracellular exosome
CC {ECO:0000269|PubMed:28740388}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q96H15-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96H15-2; Sequence=VSP_045474;
CC -!- DOMAIN: Recognizes phosphatidyl serine via its immunoglobulin domain.
CC -!- SIMILARITY: Belongs to the immunoglobulin superfamily. TIM family.
CC {ECO:0000305}.
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DR EMBL; AK301337; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AC008491; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC026777; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC008988; AAH08988.1; -; mRNA.
DR CCDS; CCDS4332.1; -. [Q96H15-1]
DR CCDS; CCDS54943.1; -. [Q96H15-2]
DR RefSeq; NP_001140198.1; NM_001146726.1. [Q96H15-2]
DR RefSeq; NP_612388.2; NM_138379.2. [Q96H15-1]
DR PDB; 5DZN; X-ray; 2.30 A; A/B/C/D/E/F/G/H=22-134.
DR PDB; 5F7F; X-ray; 1.50 A; A/B=24-134.
DR PDB; 5F7H; X-ray; 2.50 A; A/B/C/D/E/F=24-134.
DR PDBsum; 5DZN; -.
DR PDBsum; 5F7F; -.
DR PDBsum; 5F7H; -.
DR AlphaFoldDB; Q96H15; -.
DR SMR; Q96H15; -.
DR BioGRID; 124892; 14.
DR STRING; 9606.ENSP00000274532; -.
DR GlyGen; Q96H15; 1 site.
DR iPTMnet; Q96H15; -.
DR PhosphoSitePlus; Q96H15; -.
DR BioMuta; TIMD4; -.
DR DMDM; 296452930; -.
DR MassIVE; Q96H15; -.
DR PaxDb; Q96H15; -.
DR PeptideAtlas; Q96H15; -.
DR PRIDE; Q96H15; -.
DR ProteomicsDB; 6068; -.
DR ProteomicsDB; 76694; -. [Q96H15-1]
DR Antibodypedia; 2737; 454 antibodies from 37 providers.
DR DNASU; 91937; -.
DR Ensembl; ENST00000274532.7; ENSP00000274532.2; ENSG00000145850.9. [Q96H15-1]
DR Ensembl; ENST00000407087.4; ENSP00000385973.3; ENSG00000145850.9. [Q96H15-2]
DR GeneID; 91937; -.
DR KEGG; hsa:91937; -.
DR MANE-Select; ENST00000274532.7; ENSP00000274532.2; NM_138379.3; NP_612388.2.
DR UCSC; uc003lwh.2; human. [Q96H15-1]
DR CTD; 91937; -.
DR DisGeNET; 91937; -.
DR GeneCards; TIMD4; -.
DR HGNC; HGNC:25132; TIMD4.
DR HPA; ENSG00000145850; Group enriched (lymphoid tissue, testis).
DR MIM; 610096; gene.
DR neXtProt; NX_Q96H15; -.
DR OpenTargets; ENSG00000145850; -.
DR PharmGKB; PA134989118; -.
DR VEuPathDB; HostDB:ENSG00000145850; -.
DR eggNOG; ENOG502S1A2; Eukaryota.
DR GeneTree; ENSGT00940000161609; -.
DR HOGENOM; CLU_047504_0_1_1; -.
DR InParanoid; Q96H15; -.
DR OMA; QSRNSMC; -.
DR OrthoDB; 1147868at2759; -.
DR PhylomeDB; Q96H15; -.
DR TreeFam; TF336163; -.
DR PathwayCommons; Q96H15; -.
DR BioGRID-ORCS; 91937; 7 hits in 1059 CRISPR screens.
DR GeneWiki; TIMD4; -.
DR GenomeRNAi; 91937; -.
DR Pharos; Q96H15; Tbio.
DR PRO; PR:Q96H15; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; Q96H15; protein.
DR Bgee; ENSG00000145850; Expressed in left testis and 105 other tissues.
DR ExpressionAtlas; Q96H15; baseline and differential.
DR Genevisible; Q96H15; HS.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0001786; F:phosphatidylserine binding; IBA:GO_Central.
DR GO; GO:0043277; P:apoptotic cell clearance; IBA:GO_Central.
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; Alternative splicing; Cell membrane; Disulfide bond;
KW Glycoprotein; Immunoglobulin domain; Membrane; Phosphoprotein;
KW Reference proteome; Secreted; Signal; Transmembrane; Transmembrane helix.
FT SIGNAL 1..24
FT /evidence="ECO:0000255"
FT CHAIN 25..378
FT /note="T-cell immunoglobulin and mucin domain-containing
FT protein 4"
FT /id="PRO_0000042103"
FT TOPO_DOM 25..314
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 315..335
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 336..378
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 25..126
FT /note="Ig-like V-type"
FT REGION 136..160
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 269..304
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 269..301
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 358
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6U7R4"
FT CARBOHYD 291
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 40..112
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 53..64
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 59..111
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT VAR_SEQ 254..281
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_045474"
FT VARIANT 240
FT /note="V -> A (in dbSNP:rs6873053)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15489334"
FT /id="VAR_049946"
FT VARIANT 365
FT /note="V -> M (in dbSNP:rs7731575)"
FT /id="VAR_049947"
FT CONFLICT 67
FT /note="A -> T (in Ref. 1; AK301337)"
FT /evidence="ECO:0000305"
FT STRAND 25..31
FT /evidence="ECO:0007829|PDB:5F7F"
FT STRAND 36..38
FT /evidence="ECO:0007829|PDB:5F7F"
FT TURN 47..49
FT /evidence="ECO:0007829|PDB:5F7F"
FT STRAND 51..58
FT /evidence="ECO:0007829|PDB:5F7F"
FT STRAND 68..71
FT /evidence="ECO:0007829|PDB:5F7F"
FT STRAND 73..81
FT /evidence="ECO:0007829|PDB:5F7F"
FT STRAND 84..86
FT /evidence="ECO:0007829|PDB:5F7F"
FT HELIX 90..92
FT /evidence="ECO:0007829|PDB:5F7F"
FT STRAND 97..101
FT /evidence="ECO:0007829|PDB:5F7F"
FT HELIX 104..106
FT /evidence="ECO:0007829|PDB:5F7F"
FT STRAND 108..115
FT /evidence="ECO:0007829|PDB:5F7F"
FT STRAND 117..120
FT /evidence="ECO:0007829|PDB:5F7F"
FT STRAND 123..133
FT /evidence="ECO:0007829|PDB:5F7F"
SQ SEQUENCE 378 AA; 41578 MW; 6D3CC4AC89A0FE5D CRC64;
MSKEPLILWL MIEFWWLYLT PVTSETVVTE VLGHRVTLPC LYSSWSHNSN SMCWGKDQCP
YSGCKEALIR TDGMRVTSRK SAKYRLQGTI PRGDVSLTIL NPSESDSGVY CCRIEVPGWF
NDVKINVRLN LQRASTTTHR TATTTTRRTT TTSPTTTRQM TTTPAALPTT VVTTPDLTTG
TPLQMTTIAV FTTANTCLSL TPSTLPEEAT GLLTPEPSKE GPILTAESET VLPSDSWSSV
ESTSADTVLL TSKESKVWDL PSTSHVSMWK TSDSVSSPQP GASDTAVPEQ NKTTKTGQMD
GIPMSMKNEM PISQLLMIIA PSLGFVLFAL FVAFLLRGKL METYCSQKHT RLDYIGDSKN
VLNDVQHGRE DEDGLFTL
