PDCD1_MOUSE
ID PDCD1_MOUSE Reviewed; 288 AA.
AC Q02242;
DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1993, sequence version 1.
DT 03-AUG-2022, entry version 166.
DE RecName: Full=Programmed cell death protein 1 {ECO:0000303|PubMed:1396582};
DE Short=Protein PD-1 {ECO:0000303|PubMed:1396582};
DE Short=mPD-1;
DE AltName: CD_antigen=CD279;
DE Flags: Precursor;
GN Name=Pdcd1 {ECO:0000312|MGI:MGI:104879};
GN Synonyms=Pd1 {ECO:0000303|PubMed:1396582};
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], TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RX PubMed=1396582; DOI=10.1002/j.1460-2075.1992.tb05481.x;
RA Ishida Y., Agata Y., Shibahara K., Honjo T.;
RT "Induced expression of PD-1, a novel member of the immunoglobulin gene
RT superfamily, upon programmed cell death.";
RL EMBO J. 11:3887-3895(1992).
RN [2]
RP DISRUPTION PHENOTYPE.
RX PubMed=9796923; DOI=10.1093/intimm/10.10.1563;
RA Nishimura H., Minato N., Nakano T., Honjo T.;
RT "Immunological studies on PD-1 deficient mice: implication of PD-1 as a
RT negative regulator for B cell responses.";
RL Int. Immunol. 10:1563-1572(1998).
RN [3]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=10485649; DOI=10.1016/s1074-7613(00)80089-8;
RA Nishimura H., Nose M., Hiai H., Minato N., Honjo T.;
RT "Development of lupus-like autoimmune diseases by disruption of the PD-1
RT gene encoding an ITIM motif-carrying immunoreceptor.";
RL Immunity 11:141-151(1999).
RN [4]
RP FUNCTION.
RX PubMed=11015443; DOI=10.1084/jem.192.7.1027;
RA Freeman G.J., Long A.J., Iwai Y., Bourque K., Chernova T., Nishimura H.,
RA Fitz L.J., Malenkovich N., Okazaki T., Byrne M.C., Horton H.F., Fouser L.,
RA Carter L., Ling V., Bowman M.R., Carreno B.M., Collins M., Wood C.R.,
RA Honjo T.;
RT "Engagement of the PD-1 immunoinhibitory receptor by a novel B7-family
RT member leads to negative regulation of lymphocyte activation.";
RL J. Exp. Med. 192:1027-1034(2000).
RN [5]
RP FUNCTION, PHOSPHORYLATION AT TYR-225 AND TYR-248, AND MUTAGENESIS OF
RP TYR-225 AND TYR-248.
RX PubMed=11698646; DOI=10.1073/pnas.231486598;
RA Okazaki T., Maeda A., Nishimura H., Kurosaki T., Honjo T.;
RT "PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by
RT recruiting src homology 2-domain-containing tyrosine phosphatase 2 to
RT phosphotyrosine.";
RL Proc. Natl. Acad. Sci. U.S.A. 98:13866-13871(2001).
RN [6]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=11209085; DOI=10.1126/science.291.5502.319;
RA Nishimura H., Okazaki T., Tanaka Y., Nakatani K., Hara M., Matsumori A.,
RA Sasayama S., Mizoguchi A., Hiai H., Minato N., Honjo T.;
RT "Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice.";
RL Science 291:319-322(2001).
RN [7]
RP FUNCTION.
RX PubMed=11224527; DOI=10.1038/85330;
RA Latchman Y., Wood C.R., Chernova T., Chaudhary D., Borde M., Chernova I.,
RA Iwai Y., Long A.J., Brown J.A., Nunes R., Greenfield E.A., Bourque K.,
RA Boussiotis V.A., Carter L.L., Carreno B.M., Malenkovich N., Nishimura H.,
RA Okazaki T., Honjo T., Sharpe A.H., Freeman G.J.;
RT "PD-L2 is a second ligand for PD-1 and inhibits T cell activation.";
RL Nat. Immunol. 2:261-268(2001).
RN [8]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=21300912; DOI=10.1084/jem.20100466;
RA Okazaki T., Okazaki I.M., Wang J., Sugiura D., Nakaki F., Yoshida T.,
RA Kato Y., Fagarasan S., Muramatsu M., Eto T., Hioki K., Honjo T.;
RT "PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent
RT autoimmunity in mice.";
RL J. Exp. Med. 208:395-407(2011).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT TYR-225 AND TYR-248, AND
RP MUTAGENESIS OF TYR-225 AND TYR-248.
RX PubMed=22641383; DOI=10.1084/jem.20112741;
RA Yokosuka T., Takamatsu M., Kobayashi-Imanishi W., Hashimoto-Tane A.,
RA Azuma M., Saito T.;
RT "Programmed cell death 1 forms negative costimulatory microclusters that
RT directly inhibit T cell receptor signaling by recruiting phosphatase
RT SHP2.";
RL J. Exp. Med. 209:1201-1217(2012).
RN [10]
RP SUBCELLULAR LOCATION.
RX PubMed=30487606; DOI=10.1038/s41586-018-0756-0;
RA Meng X., Liu X., Guo X., Jiang S., Chen T., Hu Z., Liu H., Bai Y., Xue M.,
RA Hu R., Sun S.C., Liu X., Zhou P., Huang X., Wei L., Yang W., Xu C.;
RT "FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of
RT T cells.";
RL Nature 564:130-135(2018).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 34-150, SUBUNIT, AND DISULFIDE
RP BOND.
RX PubMed=15030777; DOI=10.1016/s1074-7613(04)00051-2;
RA Zhang X., Schwartz J.C., Guo X., Bhatia S., Cao E., Lorenz M., Cammer M.,
RA Chen L., Zhang Z.-Y., Edidin M.A., Nathenson S.G., Almo S.C.;
RT "Structural and functional analysis of the costimulatory receptor
RT programmed death-1.";
RL Immunity 20:337-347(2004).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) OF 25-157 IN COMPLEX WITH CD274,
RP FUNCTION, INTERACTION WITH CD274, AND DISULFIDE BOND.
RX PubMed=18287011; DOI=10.1073/pnas.0712278105;
RA Lin D.Y., Tanaka Y., Iwasaki M., Gittis A.G., Su H.P., Mikami B.,
RA Okazaki T., Honjo T., Minato N., Garboczi D.N.;
RT "The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of
RT antibodies and T cell receptors.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:3011-3016(2008).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 34-150 IN COMPLEX WITH PDCD1LG2,
RP FUNCTION, INTERACTION WITH PDCD1LG2, AND DISULFIDE BOND.
RX PubMed=18641123; DOI=10.1073/pnas.0804453105;
RA Lazar-Molnar E., Yan Q., Cao E., Ramagopal U., Nathenson S.G., Almo S.C.;
RT "Crystal structure of the complex between programmed death-1 (PD-1) and its
RT ligand PD-L2.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10483-10488(2008).
CC -!- FUNCTION: Inhibitory receptor on antigen activated T-cells that plays a
CC critical role in induction and maintenance of immune tolerance to self
CC (PubMed:10485649, PubMed:11698646, PubMed:11209085, PubMed:21300912).
CC Delivers inhibitory signals upon binding to ligands, such as
CC CD274/PDCD1L1 and CD273/PDCD1LG2 (PubMed:11015443, PubMed:11224527,
CC PubMed:22641383, PubMed:18287011, PubMed:18641123). Following T-cell
CC receptor (TCR) engagement, PDCD1 associates with CD3-TCR in the
CC immunological synapse and directly inhibits T-cell activation
CC (PubMed:22641383). Suppresses T-cell activation through the recruitment
CC of PTPN11/SHP-2: following ligand-binding, PDCD1 is phosphorylated
CC within the ITSM motif, leading to the recruitment of the protein
CC tyrosine phosphatase PTPN11/SHP-2 that mediates dephosphorylation of
CC key TCR proximal signaling molecules, such as ZAP70, PRKCQ/PKCtheta and
CC CD247/CD3zeta (PubMed:11698646, PubMed:22641383). The PDCD1-mediated
CC inhibitory pathway is exploited by tumors to attenuate anti-tumor
CC immunity and facilitate tumor survival (By similarity).
CC {ECO:0000250|UniProtKB:Q15116, ECO:0000269|PubMed:10485649,
CC ECO:0000269|PubMed:11015443, ECO:0000269|PubMed:11209085,
CC ECO:0000269|PubMed:11224527, ECO:0000269|PubMed:11698646,
CC ECO:0000269|PubMed:18287011, ECO:0000269|PubMed:18641123,
CC ECO:0000269|PubMed:21300912, ECO:0000269|PubMed:22641383}.
CC -!- SUBUNIT: Monomer (PubMed:15030777, PubMed:18287011, PubMed:18641123).
CC Interacts with CD274/PDCD1L1 (PubMed:18287011). Interacts with
CC CD273/PDCD1LG2 (PubMed:18641123). Interacts with FBXO38; leading to
CC ubiquitination and degradation by the proteasome (By similarity).
CC {ECO:0000250|UniProtKB:Q15116, ECO:0000269|PubMed:15030777,
CC ECO:0000269|PubMed:18287011, ECO:0000269|PubMed:18641123}.
CC -!- INTERACTION:
CC Q02242; Q9EP73: Cd274; NbExp=3; IntAct=EBI-5258903, EBI-5258879;
CC Q02242; Q9WUL5: Pdcd1lg2; NbExp=2; IntAct=EBI-5258903, EBI-15716794;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:22641383,
CC ECO:0000269|PubMed:30487606}; Single-pass type I membrane protein.
CC -!- TISSUE SPECIFICITY: Thymus-specific. {ECO:0000269|PubMed:1396582}.
CC -!- DEVELOPMENTAL STAGE: Induced at programmed cell death.
CC {ECO:0000269|PubMed:1396582}.
CC -!- PTM: Ubiquitinated at Lys-235 by the SCF(FBXO38) complex, leading to
CC its proteasomal degradation. Ubiquitinated via 'Lys-48'-linked
CC polyubiquitin chains. {ECO:0000250|UniProtKB:Q15116}.
CC -!- PTM: Tyrosine phosphorylated at Tyr-225 (within ITIM motif) and Tyr-248
CC (ITSM motif) upon ligand binding (PubMed:11698646, PubMed:22641383).
CC Phosphorylation at Tyr-248 promotes the recruitment of the protein
CC tyrosine phosphatase PTPN11/SHP-2 that mediates dephosphorylation of
CC key TCR proximal signaling molecules, such as ZAP70, PRKCQ/PKCtheta and
CC CD247/CD3zeta (PubMed:22641383). {ECO:0000269|PubMed:11698646,
CC ECO:0000269|PubMed:22641383}.
CC -!- DISRUPTION PHENOTYPE: Mice grow and develop normally but exhibit
CC splenomegaly, selective augmentation of IgG3 antibody response to a T-
CC independent type II antigen, and enhanced proliferative responses of B-
CC cells and myeloid cells by anti-IgM and granulocyte colony-stimulating
CC factor stimulation (PubMed:9796923). Mice are prone to development of
CC autoimmune diseases (PubMed:10485649, PubMed:11209085). In a C57BL/6J
CC background, mice spontaneously develop lupus-like autoimmune
CC phenotypes, characterized by proliferative arthritis and
CC glomerulonephritis with predominant IgG3 deposition (PubMed:10485649).
CC In a BALB/c background, mice develop autoimmune dilated cardiomyopathy
CC with severely impaired contraction, and two-third of mice die by
CC congestive heart failure before 30 weeks of age (PubMed:11209085). Mice
CC lacking both Lag3 and Pdcd1/PD-1 die of severe myocarditis before 10
CC weeks of age in BALB/c mice (PubMed:21300912).
CC {ECO:0000269|PubMed:10485649, ECO:0000269|PubMed:11209085,
CC ECO:0000269|PubMed:21300912, ECO:0000269|PubMed:9796923}.
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DR EMBL; X67914; CAA48113.1; -; mRNA.
DR CCDS; CCDS15200.1; -.
DR PIR; S28029; S28029.
DR RefSeq; NP_032824.1; NM_008798.2.
DR PDB; 1NPU; X-ray; 2.00 A; A=34-150.
DR PDB; 3BIK; X-ray; 2.65 A; B/C=25-157.
DR PDB; 3BP5; X-ray; 1.80 A; A=34-150.
DR PDB; 3BP6; X-ray; 1.60 A; A=34-150.
DR PDB; 3RNK; X-ray; 1.74 A; A=34-150.
DR PDB; 3RNQ; X-ray; 1.60 A; A=34-150.
DR PDB; 3SBW; X-ray; 2.28 A; A/B=34-150.
DR PDBsum; 1NPU; -.
DR PDBsum; 3BIK; -.
DR PDBsum; 3BP5; -.
DR PDBsum; 3BP6; -.
DR PDBsum; 3RNK; -.
DR PDBsum; 3RNQ; -.
DR PDBsum; 3SBW; -.
DR AlphaFoldDB; Q02242; -.
DR SMR; Q02242; -.
DR DIP; DIP-29730N; -.
DR IntAct; Q02242; 4.
DR STRING; 10090.ENSMUSP00000027507; -.
DR BindingDB; Q02242; -.
DR ChEMBL; CHEMBL4630756; -.
DR GlyGen; Q02242; 4 sites.
DR iPTMnet; Q02242; -.
DR PhosphoSitePlus; Q02242; -.
DR SwissPalm; Q02242; -.
DR PaxDb; Q02242; -.
DR PRIDE; Q02242; -.
DR ProteomicsDB; 287899; -.
DR ABCD; Q02242; 7 sequenced antibodies.
DR Antibodypedia; 20331; 2509 antibodies from 52 providers.
DR DNASU; 18566; -.
DR Ensembl; ENSMUST00000027507; ENSMUSP00000027507; ENSMUSG00000026285.
DR GeneID; 18566; -.
DR KEGG; mmu:18566; -.
DR UCSC; uc007cev.1; mouse.
DR CTD; 5133; -.
DR MGI; MGI:104879; Pdcd1.
DR VEuPathDB; HostDB:ENSMUSG00000026285; -.
DR eggNOG; ENOG502SUIW; Eukaryota.
DR GeneTree; ENSGT00390000013662; -.
DR HOGENOM; CLU_1075828_0_0_1; -.
DR InParanoid; Q02242; -.
DR OMA; HTEYATI; -.
DR OrthoDB; 1437063at2759; -.
DR PhylomeDB; Q02242; -.
DR TreeFam; TF336181; -.
DR Reactome; R-MMU-389948; PD-1 signaling.
DR BioGRID-ORCS; 18566; 4 hits in 76 CRISPR screens.
DR EvolutionaryTrace; Q02242; -.
DR PRO; PR:Q02242; -.
DR Proteomes; UP000000589; Chromosome 1.
DR RNAct; Q02242; protein.
DR Bgee; ENSMUSG00000026285; Expressed in thymus and 23 other tissues.
DR ExpressionAtlas; Q02242; baseline and differential.
DR Genevisible; Q02242; MM.
DR GO; GO:0009897; C:external side of plasma membrane; IDA:MGI.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0002250; P:adaptive immune response; IEA:UniProtKB-KW.
DR GO; GO:0001783; P:B cell apoptotic process; IMP:MGI.
DR GO; GO:0002903; P:negative regulation of B cell apoptotic process; IMP:MGI.
DR GO; GO:0050777; P:negative regulation of immune response; IMP:UniProtKB.
DR GO; GO:0002644; P:negative regulation of tolerance induction; IMP:MGI.
DR GO; GO:0070234; P:positive regulation of T cell apoptotic process; IMP:MGI.
DR GO; GO:0050776; P:regulation of immune response; IBA:GO_Central.
DR GO; GO:1902482; P:regulatory T cell apoptotic process; IMP:MGI.
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 InterPro; IPR042379; PDCD1.
DR PANTHER; PTHR15264; PTHR15264; 1.
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; Adaptive immunity; Apoptosis; Cell membrane; Disulfide bond;
KW Glycoprotein; Immunity; Immunoglobulin domain; Isopeptide bond; Membrane;
KW Phosphoprotein; Reference proteome; Signal; Transmembrane;
KW Transmembrane helix; Ubl conjugation.
FT SIGNAL 1..24
FT /evidence="ECO:0000255"
FT CHAIN 25..288
FT /note="Programmed cell death protein 1"
FT /id="PRO_0000014893"
FT TOPO_DOM 25..169
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 170..190
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 191..288
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 31..139
FT /note="Ig-like V-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT REGION 70..77
FT /note="Interaction with CD274/PDCD1L1"
FT /evidence="ECO:0000250|UniProtKB:Q15116"
FT REGION 263..288
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 223..228
FT /note="ITIM motif"
FT /evidence="ECO:0000269|PubMed:11698646,
FT ECO:0000269|PubMed:22641383"
FT MOTIF 247..251
FT /note="ITSM motif"
FT /evidence="ECO:0000269|PubMed:22641383"
FT MOD_RES 225
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:11698646"
FT MOD_RES 248
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:11698646"
FT CARBOHYD 49
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 58
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 74
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 116
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 54..123
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114,
FT ECO:0000269|PubMed:15030777, ECO:0000269|PubMed:18287011,
FT ECO:0000269|PubMed:18641123"
FT CROSSLNK 235
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q15116"
FT MUTAGEN 225
FT /note="Y->F: Reduced tyrosine phosphorylation. Decreased
FT ability to mediate recruitment of PTPN11/SHP-2."
FT /evidence="ECO:0000269|PubMed:11698646,
FT ECO:0000269|PubMed:22641383"
FT MUTAGEN 248
FT /note="Y->F: Reduced tyrosine phosphorylation. Abolished
FT ability to mediate recruitment of PTPN11/SHP-2."
FT /evidence="ECO:0000269|PubMed:11698646,
FT ECO:0000269|PubMed:22641383"
FT STRAND 35..38
FT /evidence="ECO:0007829|PDB:3BP6"
FT STRAND 40..45
FT /evidence="ECO:0007829|PDB:3BP6"
FT STRAND 50..58
FT /evidence="ECO:0007829|PDB:3BP6"
FT STRAND 64..70
FT /evidence="ECO:0007829|PDB:3BP6"
FT STRAND 76..83
FT /evidence="ECO:0007829|PDB:3BP6"
FT STRAND 86..91
FT /evidence="ECO:0007829|PDB:3BP6"
FT STRAND 95..99
FT /evidence="ECO:0007829|PDB:3BP6"
FT STRAND 103..112
FT /evidence="ECO:0007829|PDB:3BP6"
FT HELIX 115..117
FT /evidence="ECO:0007829|PDB:3BP6"
FT STRAND 119..127
FT /evidence="ECO:0007829|PDB:3BP6"
FT STRAND 129..131
FT /evidence="ECO:0007829|PDB:3BP6"
FT STRAND 133..136
FT /evidence="ECO:0007829|PDB:3BP6"
FT STRAND 140..145
FT /evidence="ECO:0007829|PDB:3BP6"
SQ SEQUENCE 288 AA; 31842 MW; 4AD3C5F0F9D4200A CRC64;
MWVRQVPWSF TWAVLQLSWQ SGWLLEVPNG PWRSLTFYPA WLTVSEGANA TFTCSLSNWS
EDLMLNWNRL SPSNQTEKQA AFCNGLSQPV QDARFQIIQL PNRHDFHMNI LDTRRNDSGI
YLCGAISLHP KAKIEESPGA ELVVTERILE TSTRYPSPSP KPEGRFQGMV IGIMSALVGI
PVLLLLAWAL AVFCSTSMSE ARGAGSKDDT LKEEPSAAPV PSVAYEELDF QGREKTPELP
TACVHTEYAT IVFTEGLGAS AMGRRGSADG LQGPRPPRHE DGHCSWPL
