ID   BTLA_MOUSE              Reviewed;         306 AA.
AC   Q7TSA3;
DT   19-JUL-2005, integrated into UniProtKB/Swiss-Prot.
DT   19-JUL-2005, sequence version 2.
DT   24-JAN-2024, entry version 137.
DE   RecName: Full=B- and T-lymphocyte attenuator {ECO:0000303|PubMed:14652006};
DE   AltName: Full=B- and T-lymphocyte-associated protein;
DE   AltName: CD_antigen=CD272;
DE   Flags: Precursor;
GN   Name=Btla {ECO:0000303|PubMed:12796776, ECO:0000312|MGI:MGI:2658978};
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] (ISOFORMS 1 AND 2), MUTAGENESIS OF TYR-245;
RP   TYR-274 AND TYR-299, GLYCOSYLATION, TISSUE SPECIFICITY, INTERACTION WITH
RP   PTPN6 AND PTPN11, DISRUPTION PHENOTYPE, VARIANTS GLU-41; 45-THR--THR-47
RP   DELINS ASN-ILE-LYS; HIS-52; TRP-55; GLU-63; TRP-85; GLY-91 AND ARG-102,
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RC   STRAIN=129/SvEv;
RX   PubMed=12796776; DOI=10.1038/ni944;
RA   Watanabe N., Gavrieli M., Sedy J.R., Yang J., Fallarino F., Loftin S.K.,
RA   Hurchla M.A., Zimmerman N., Sim J., Zang X., Murphy T.L., Russell J.H.,
RA   Allison J.P., Murphy K.M.;
RT   "BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and
RT   PD-1.";
RL   Nat. Immunol. 4:670-679(2003).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), AND VARIANT THR-143.
RC   STRAIN=C57BL/6J; TISSUE=Thymus;
RX   PubMed=16141072; DOI=10.1126/science.1112014;
RA   Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA   Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA   Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA   Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA   Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA   Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA   Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA   Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA   Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA   Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA   Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA   Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA   Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA   Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA   Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA   Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA   Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA   Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA   Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA   Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA   Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA   Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA   Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA   Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA   Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA   van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA   Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA   Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA   Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA   Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA   Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA   Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA   Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA   Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT   "The transcriptional landscape of the mammalian genome.";
RL   Science 309:1559-1563(2005).
RN   [3]
RP   MUTAGENESIS OF TYR-245; TYR-274 AND TYR-299, INTERACTION WITH PTPN6 AND
RP   PTPN11, AND FUNCTION.
RX   PubMed=14652006; DOI=10.1016/j.bbrc.2003.11.070;
RA   Gavrieli M., Watanabe N., Loftin S.K., Murphy T.L., Murphy K.M.;
RT   "Characterization of phosphotyrosine binding motifs in the cytoplasmic
RT   domain of B and T lymphocyte attenuator required for association with
RT   protein tyrosine phosphatases SHP-1 and SHP-2.";
RL   Biochem. Biophys. Res. Commun. 312:1236-1243(2003).
RN   [4]
RP   INTERACTION WITH TNFRSF14, AND PHOSPHORYLATION.
RX   PubMed=15568026; DOI=10.1038/ni1144;
RA   Sedy J.R., Gavrieli M., Potter K.G., Hurchla M.A., Lindsley R.C.,
RA   Hildner K., Scheu S., Pfeffer K., Ware C.F., Murphy T.L., Murphy K.M.;
RT   "B and T lymphocyte attenuator regulates T cell activation through
RT   interaction with herpesvirus entry mediator.";
RL   Nat. Immunol. 6:90-98(2005).
RN   [5]
RP   TISSUE SPECIFICITY, AND POLYMORPHISM.
RX   PubMed=15749870; DOI=10.4049/jimmunol.174.6.3377;
RA   Hurchla M.A., Sedy J.R., Gavrieli M., Drake C.G., Murphy T.L., Murphy K.M.;
RT   "B and T lymphocyte attenuator exhibits structural and expression
RT   polymorphisms and is highly induced in anergic CD4+ T cells.";
RL   J. Immunol. 174:3377-3385(2005).
RN   [6]
RP   FUNCTION, SUBUNIT, AND INTERACTION WITH TNFRSF14.
RX   PubMed=19915044; DOI=10.4049/jimmunol.0902490;
RA   Cheung T.C., Oborne L.M., Steinberg M.W., Macauley M.G., Fukuyama S.,
RA   Sanjo H., D'Souza C., Norris P.S., Pfeffer K., Murphy K.M., Kronenberg M.,
RA   Spear P.G., Ware C.F.;
RT   "T cell intrinsic heterodimeric complexes between HVEM and BTLA determine
RT   receptivity to the surrounding microenvironment.";
RL   J. Immunol. 183:7286-7296(2009).
RN   [7]
RP   X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 30-150, MUTAGENESIS OF LEU-44;
RP   ARG-48; PRO-65 AND HIS-136, INTERACTION WITH TNFRSF14/HVEM, AND DISULFIDE
RP   BONDS.
RX   PubMed=18178834; DOI=10.4049/jimmunol.180.2.940;
RA   Nelson C.A., Fremont M.D., Sedy J.R., Norris P.S., Ware C.F., Murphy K.M.,
RA   Fremont D.H.;
RT   "Structural determinants of herpesvirus entry mediator recognition by
RT   murine B and T lymphocyte attenuator.";
RL   J. Immunol. 180:940-947(2008).
CC   -!- FUNCTION: Inhibitory receptor on lymphocytes that negatively regulates
CC       antigen receptor signaling via PTPN6/SHP-1 and PTPN11/SHP-2
CC       (PubMed:12796776, PubMed:14652006). May interact in cis (on the same
CC       cell) or in trans (on other cells) with TNFRSF14 (PubMed:19915044). In
CC       cis interactions, appears to play an immune regulatory role inhibiting
CC       in trans interactions in naive T cells to maintain a resting state. In
CC       trans interactions, can predominate during adaptive immune response to
CC       provide survival signals to effector T cells (PubMed:19915044).
CC       {ECO:0000269|PubMed:12796776, ECO:0000269|PubMed:14652006,
CC       ECO:0000269|PubMed:19915044}.
CC   -!- SUBUNIT: Interacts with tyrosine phosphatases PTPN6/SHP-1 and
CC       PTPN11/SHP-2 (PubMed:12796776, PubMed:14652006). Interacts with
CC       TNFRSF14/HVEM (via cysteine-rich domain 1) (PubMed:19915044).
CC       {ECO:0000269|PubMed:12796776, ECO:0000269|PubMed:14652006,
CC       ECO:0000269|PubMed:15568026, ECO:0000269|PubMed:18178834,
CC       ECO:0000269|PubMed:19915044}.
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:12796776};
CC       Single-pass type I membrane protein {ECO:0000305}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC       Name=1;
CC         IsoId=Q7TSA3-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q7TSA3-2; Sequence=VSP_014836;
CC       Name=3;
CC         IsoId=Q7TSA3-3; Sequence=VSP_014837;
CC   -!- TISSUE SPECIFICITY: Expressed in splenic T- and B-cells as well as
CC       lymph node tissues but very weakly in somatic tissues. Also expressed
CC       in macrophages, NK cells and dendritic cells. A polymorphic tissue
CC       distribution between several strains is seen.
CC       {ECO:0000269|PubMed:12796776, ECO:0000269|PubMed:15749870}.
CC   -!- PTM: Phosphorylated on Tyr residues by TNFRSF14 and by antigen
CC       receptors cross-linking, both inducing association with PTPN6 and
CC       PTPN11. {ECO:0000269|PubMed:15568026}.
CC   -!- PTM: N-glycosylated. {ECO:0000269|PubMed:12796776}.
CC   -!- DISRUPTION PHENOTYPE: Mice exhibit no developmental defects in T- or B-
CC       cells in thymus or bone marrow, but increased antibody responses and
CC       sensitivity to antigen-induced 'experimental autoimmune
CC       encephalomyelitis'. T-cells lacking Btla show increased proliferation
CC       with a heightened response to anti-CD3 and a slightly greater response
CC       to stimulation with anti-IgM. {ECO:0000269|PubMed:12796776}.
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DR   EMBL; AY293285; AAP44002.1; -; mRNA.
DR   EMBL; AK041334; BAC30910.1; -; mRNA.
DR   CCDS; CCDS28195.1; -. [Q7TSA3-1]
DR   CCDS; CCDS28196.1; -. [Q7TSA3-3]
DR   RefSeq; NP_001032808.2; NM_001037719.2.
DR   RefSeq; NP_808252.1; NM_177584.3.
DR   PDB; 1XAU; X-ray; 1.80 A; A=30-150.
DR   PDBsum; 1XAU; -.
DR   AlphaFoldDB; Q7TSA3; -.
DR   SMR; Q7TSA3; -.
DR   BioGRID; 228954; 3.
DR   STRING; 10090.ENSMUSP00000067877; -.
DR   GlyCosmos; Q7TSA3; 6 sites, No reported glycans.
DR   GlyGen; Q7TSA3; 6 sites.
DR   iPTMnet; Q7TSA3; -.
DR   PhosphoSitePlus; Q7TSA3; -.
DR   PaxDb; 10090-ENSMUSP00000099866; -.
DR   ProteomicsDB; 265317; -. [Q7TSA3-1]
DR   ProteomicsDB; 265318; -. [Q7TSA3-2]
DR   ProteomicsDB; 265319; -. [Q7TSA3-3]
DR   ABCD; Q7TSA3; 9 sequenced antibodies.
DR   GeneID; 208154; -.
DR   KEGG; mmu:208154; -.
DR   UCSC; uc007zik.1; mouse. [Q7TSA3-3]
DR   AGR; MGI:2658978; -.
DR   CTD; 151888; -.
DR   MGI; MGI:2658978; Btla.
DR   eggNOG; ENOG502SGTG; Eukaryota.
DR   InParanoid; Q7TSA3; -.
DR   OrthoDB; 5359457at2759; -.
DR   PhylomeDB; Q7TSA3; -.
DR   TreeFam; TF337694; -.
DR   Reactome; R-MMU-388841; Costimulation by the CD28 family.
DR   BioGRID-ORCS; 208154; 1 hit in 81 CRISPR screens.
DR   EvolutionaryTrace; Q7TSA3; -.
DR   PRO; PR:Q7TSA3; -.
DR   Proteomes; UP000000589; Unplaced.
DR   RNAct; Q7TSA3; Protein.
DR   GO; GO:0009897; C:external side of plasma membrane; IDA:MGI.
DR   GO; GO:0005886; C:plasma membrane; IDA:MGI.
DR   GO; GO:0038023; F:signaling receptor activity; IGI:MGI.
DR   GO; GO:0002250; P:adaptive immune response; IEA:UniProtKB-KW.
DR   GO; GO:0007166; P:cell surface receptor signaling pathway; IDA:MGI.
DR   GO; GO:0002768; P:immune response-regulating cell surface receptor signaling pathway; IMP:MGI.
DR   GO; GO:0046642; P:negative regulation of alpha-beta T cell proliferation; IMP:MGI.
DR   GO; GO:0030889; P:negative regulation of B cell proliferation; IMP:MGI.
DR   GO; GO:0042130; P:negative regulation of T cell proliferation; IMP:MGI.
DR   Gene3D; 2.60.40.10; Immunoglobulins; 1.
DR   InterPro; IPR039257; BTLA.
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   PANTHER; PTHR37996; B- AND T-LYMPHOCYTE ATTENUATOR; 1.
DR   PANTHER; PTHR37996:SF1; B- AND T-LYMPHOCYTE ATTENUATOR; 1.
DR   SMART; SM00409; IG; 1.
DR   SUPFAM; SSF48726; Immunoglobulin; 1.
DR   PROSITE; PS50835; IG_LIKE; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Adaptive immunity; Alternative splicing; Cell membrane;
KW   Disulfide bond; Glycoprotein; Immunity; Immunoglobulin domain; Membrane;
KW   Phosphoprotein; Receptor; Reference proteome; Signal; Transmembrane;
KW   Transmembrane helix.
FT   SIGNAL          1..29
FT                   /evidence="ECO:0000255"
FT   CHAIN           30..306
FT                   /note="B- and T-lymphocyte attenuator"
FT                   /id="PRO_0000014524"
FT   TOPO_DOM        30..183
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        184..204
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        205..306
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          37..139
FT                   /note="Ig-like V-type"
FT   CARBOHYD        74
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        81
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        101
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        119
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        148
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        165
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        40..69
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00114,
FT                   ECO:0000269|PubMed:18178834"
FT   DISULFID        64..124
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00114,
FT                   ECO:0000269|PubMed:18178834"
FT   DISULFID        78..85
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00114,
FT                   ECO:0000269|PubMed:18178834"
FT   VAR_SEQ         37..142
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:12796776"
FT                   /id="VSP_014836"
FT   VAR_SEQ         156..157
FT                   /note="TV -> I (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:16141072"
FT                   /id="VSP_014837"
FT   VARIANT         41
FT                   /note="P -> E (in strain: 129/SvEv; requires 2 nucleotide
FT                   substitutions)"
FT                   /evidence="ECO:0000269|PubMed:12796776"
FT   VARIANT         45..47
FT                   /note="TIT -> NIK (in strain: 129/SvEv)"
FT                   /evidence="ECO:0000269|PubMed:12796776"
FT   VARIANT         52
FT                   /note="Q -> H (in strain: 129/SvEv)"
FT                   /evidence="ECO:0000269|PubMed:12796776"
FT   VARIANT         55
FT                   /note="R -> W (in strain: 129/SvEv)"
FT                   /evidence="ECO:0000269|PubMed:12796776"
FT   VARIANT         63
FT                   /note="Q -> E (in strain: 129/SvEv)"
FT                   /evidence="ECO:0000269|PubMed:12796776"
FT   VARIANT         85
FT                   /note="C -> W (in strain: 129/SvEv)"
FT                   /evidence="ECO:0000269|PubMed:12796776"
FT   VARIANT         91
FT                   /note="S -> G (in strain: 129/SvEv)"
FT                   /evidence="ECO:0000269|PubMed:12796776"
FT   VARIANT         102
FT                   /note="Q -> R (in strain: 129/SvEv)"
FT                   /evidence="ECO:0000269|PubMed:12796776"
FT   VARIANT         143
FT                   /note="R -> T (in strain: C57BL/6J)"
FT                   /evidence="ECO:0000269|PubMed:16141072"
FT   MUTAGEN         44
FT                   /note="L->H: Loss of interaction with TNFRSF14."
FT                   /evidence="ECO:0000269|PubMed:18178834"
FT   MUTAGEN         48
FT                   /note="R->D: Loss of interaction with TNFRSF14."
FT                   /evidence="ECO:0000269|PubMed:18178834"
FT   MUTAGEN         65
FT                   /note="P->A: Loss of interaction with TNFRSF14."
FT                   /evidence="ECO:0000269|PubMed:18178834"
FT   MUTAGEN         136
FT                   /note="H->D: Loss of interaction with TNFRSF14."
FT                   /evidence="ECO:0000269|PubMed:18178834"
FT   MUTAGEN         245
FT                   /note="Y->F: No change of phosphorylation implicated in
FT                   interaction with PTPN6 and PTPN11. Severe reduction of
FT                   phosphorylation; when associated with F-274 and/or F-299."
FT                   /evidence="ECO:0000269|PubMed:12796776,
FT                   ECO:0000269|PubMed:14652006"
FT   MUTAGEN         274
FT                   /note="Y->F: No change of phosphorylation implicated in
FT                   interaction with PTPN6 and PTPN11. Severe reduction of
FT                   phosphorylation; when associated with F-245 and/or F-299."
FT                   /evidence="ECO:0000269|PubMed:12796776,
FT                   ECO:0000269|PubMed:14652006"
FT   MUTAGEN         299
FT                   /note="Y->F: No change of phosphorylation implicated in
FT                   interaction with PTPN6 and PTPN11. Severe reduction of
FT                   phosphorylation; when associated with F-245 and/or F-274."
FT                   /evidence="ECO:0000269|PubMed:12796776,
FT                   ECO:0000269|PubMed:14652006"
FT   STRAND          50..55
FT                   /evidence="ECO:0007829|PDB:1XAU"
FT   STRAND          60..67
FT                   /evidence="ECO:0007829|PDB:1XAU"
FT   STRAND          69..71
FT                   /evidence="ECO:0007829|PDB:1XAU"
FT   STRAND          75..80
FT                   /evidence="ECO:0007829|PDB:1XAU"
FT   STRAND          82..87
FT                   /evidence="ECO:0007829|PDB:1XAU"
FT   STRAND          94..99
FT                   /evidence="ECO:0007829|PDB:1XAU"
FT   STRAND          101..104
FT                   /evidence="ECO:0007829|PDB:1XAU"
FT   STRAND          106..111
FT                   /evidence="ECO:0007829|PDB:1XAU"
FT   HELIX           116..118
FT                   /evidence="ECO:0007829|PDB:1XAU"
FT   STRAND          120..128
FT                   /evidence="ECO:0007829|PDB:1XAU"
FT   STRAND          131..134
FT                   /evidence="ECO:0007829|PDB:1XAU"
FT   STRAND          138..143
FT                   /evidence="ECO:0007829|PDB:1XAU"
SQ   SEQUENCE   306 AA;  34337 MW;  A5B4584BAC882B93 CRC64;
     MKTVPAMLGT PRLFREFFIL HLGLWSILCE KATKRNDEEC PVQLTITRNS KQSARTGELF
     KIQCPVKYCV HRPNVTWCKH NGTICVPLEV SPQLYTSWEE NQSVPVFVLH FKPIHLSDNG
     SYSCSTNFNS QVINSHSVTI HVRERTQNSS EHPLITVSDI PDATNASGPS TMEERPGRTW
     LLYTLLPLGA LLLLLACVCL LCFLKRIQGK EKKPSDLAGR DTNLVDIPAS SRTNHQALPS
     GTGIYDNDPW SSMQDESELT ISLQSERNNQ GIVYASLNHC VIGRNPRQEN NMQEAPTEYA
     SICVRS
//