ID PDCD1_HUMAN Reviewed; 288 AA. AC Q15116; O00517; Q8IX89; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 17-APR-2007, sequence version 3. DT 02-SEP-2026, entry version 208. DE RecName: Full=Programmed cell death protein 1 {ECO:0000303|PubMed:7851902}; DE Short=Protein PD-1 {ECO:0000303|PubMed:7851902}; DE Short=hPD-1 {ECO:0000303|PubMed:26602187, ECO:0000303|PubMed:9332365}; DE AltName: CD_antigen=CD279; DE Flags: Precursor; GN Name=PDCD1 {ECO:0000303|PubMed:7851902, ECO:0000312|HGNC:HGNC:8760}; GN Synonyms=PD1 {ECO:0000303|PubMed:7851902}; 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 [GENOMIC DNA]. RX PubMed=7851902; DOI=10.1006/geno.1994.1562; RA Shinohara T., Taniwaki M., Ishida Y., Kawaich M., Honjo T.; RT "Structure and chromosomal localization of the human PD-1 gene (PDCD1)."; RL Genomics 23:704-706(1994). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=9332365; DOI=10.1016/s0378-1119(97)00260-6; RA Finger L.R., Pu J., Wasserman R., Vibhakar R., Louie E., Hardy R.R., RA Burrows P.D., Billips L.D.; RT "The human PD-1 gene: complete cDNA, genomic organization, and RT developmentally regulated expression in B cell progenitors."; RL Gene 197:177-187(1997). RN [3] RP ERRATUM OF PUBMED:9332365. RA Finger L.R., Pu J., Wasserman R., Vibhakar R., Louie E., Hardy R.R., RA Burrows P.D., Billips L.D.; RL Gene 203:253-253(1997). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=12402038; DOI=10.1038/ng1020; RA Prokunina L., Castillejo-Lopez C., Oberg F., Gunnarsson I., Berg L., RA Magnusson V., Brookes A.J., Tentler D., Kristjansdottir H., Grondal G., RA Bolstad A.I., Svenungsson E., Lundberg I., Sturfelt G., Jonssen A., RA Truedsson L., Lima G., Alcocer-Varela J., Jonsson R., Gyllensten U.B., RA Harley J.B., Alarcon-Segovia D., Steinsson K., Alarcon-Riquelme M.E.; RT "A regulatory polymorphism in PDCD1 is associated with susceptibility to RT systemic lupus erythematosus in humans."; RL Nat. Genet. 32:666-669(2002). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA]. RA He X., Xu L., Liu Y., Zeng Y.; RT "Cloning of PD-1 cDNA from activated peripheral leukocytes."; RL Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Livingston R.J., Shaffer T., McFarland I., Nguyen C.P., Stanaway I.B., RA Rajkumar N., Johnson E.J., da Ponte S.H., Willa H., Ahearn M.O., RA Bertucci C., Acklestad J., Carroll A., Swanson J., Gildersleeve H.I., RA Nickerson D.A.; RL Submitted (OCT-2006) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [10] RP FUNCTION. RX PubMed=21276005; DOI=10.1111/j.1749-6632.2010.05919.x; RA Fife B.T., Pauken K.E.; RT "The role of the PD-1 pathway in autoimmunity and peripheral tolerance."; RL Ann. N. Y. Acad. Sci. 1217:45-59(2011). RN [11] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=22658127; DOI=10.1056/nejmoa1200690; RA Topalian S.L., Hodi F.S., Brahmer J.R., Gettinger S.N., Smith D.C., RA McDermott D.F., Powderly J.D., Carvajal R.D., Sosman J.A., Atkins M.B., RA Leming P.D., Spigel D.R., Antonia S.J., Horn L., Drake C.G., Pardoll D.M., RA Chen L., Sharfman W.H., Anders R.A., Taube J.M., McMiller T.L., Xu H., RA Korman A.J., Jure-Kunkel M., Agrawal S., McDonald D., Kollia G.D., RA Gupta A., Wigginton J.M., Sznol M.; RT "Safety, activity, and immune correlates of anti-PD-1 antibody in cancer."; RL N. Engl. J. Med. 366:2443-2454(2012). RN [12] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=25034862; DOI=10.1016/s0140-6736(14)60958-2; RA Robert C., Ribas A., Wolchok J.D., Hodi F.S., Hamid O., Kefford R., RA Weber J.S., Joshua A.M., Hwu W.J., Gangadhar T.C., Patnaik A., Dronca R., RA Zarour H., Joseph R.W., Boasberg P., Chmielowski B., Mateus C., RA Postow M.A., Gergich K., Elassaiss-Schaap J., Li X.N., Iannone R., RA Ebbinghaus S.W., Kang S.P., Daud A.; RT "Anti-programmed-death-receptor-1 treatment with pembrolizumab in RT ipilimumab-refractory advanced melanoma: a randomised dose-comparison RT cohort of a phase 1 trial."; RL Lancet 384:1109-1117(2014). RN [13] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=25399552; DOI=10.1056/nejmoa1412082; RA Robert C., Long G.V., Brady B., Dutriaux C., Maio M., Mortier L., RA Hassel J.C., Rutkowski P., McNeil C., Kalinka-Warzocha E., Savage K.J., RA Hernberg M.M., Lebbe C., Charles J., Mihalcioiu C., Chiarion-Sileni V., RA Mauch C., Cognetti F., Arance A., Schmidt H., Schadendorf D., Gogas H., RA Lundgren-Eriksson L., Horak C., Sharkey B., Waxman I.M., Atkinson V., RA Ascierto P.A.; RT "Nivolumab in previously untreated melanoma without BRAF mutation."; RL N. Engl. J. Med. 372:320-330(2015). RN [14] RP UBIQUITINATION AT LYS-233, SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-210 RP AND LYS-233. 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 [15] RP REVIEW. RX PubMed=28951311; DOI=10.1016/j.gene.2017.09.050; RA Berger K.N., Pu J.J.; RT "PD-1 pathway and its clinical application: A 20year journey after RT discovery of the complete human PD-1 gene."; RL Gene 638:20-25(2018). RN [16] RP FUNCTION, SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT TYR-248. RX PubMed=31754127; DOI=10.1038/s41598-019-53463-0; RA Bardhan K., Aksoylar H.I., Le Bourgeois T., Strauss L., Weaver J.D., RA Delcuze B., Charest A., Patsoukis N., Boussiotis V.A.; RT "Phosphorylation of PD-1-Y248 is a marker of PD-1-mediated inhibitory RT function in human T cells."; RL Sci. Rep. 9:17252-17252(2019). RN [17] RP FUNCTION, PHOSPHORYLATION AT TYR-223 AND TYR-248, AND MUTAGENESIS OF RP TYR-223 AND TYR-248. RX PubMed=32184441; DOI=10.1038/s42003-020-0845-0; RA Patsoukis N., Duke-Cohan J.S., Chaudhri A., Aksoylar H.I., Wang Q., RA Council A., Berg A., Freeman G.J., Boussiotis V.A.; RT "Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization RT and SHP-2 activation."; RL Commun. Biol. 3:128-128(2020). RN [18] RP INVOLVEMENT IN ADMIO4. RX PubMed=34183838; DOI=10.1038/s41591-021-01388-5; RA Ogishi M., Yang R., Aytekin C., Langlais D., Bourgey M., Khan T., Ali F.A., RA Rahman M., Delmonte O.M., Chrabieh M., Zhang P., Gruber C., Pelham S.J., RA Spaan A.N., Rosain J., Lei W.T., Drutman S., Hellmann M.D., Callahan M.K., RA Adamow M., Wong P., Wolchok J.D., Rao G., Ma C.S., Nakajima Y., Yaguchi T., RA Chamoto K., Williams S.C., Emile J.F., Rozenberg F., Glickman M.S., RA Rapaport F., Kerner G., Allington G., Tezcan I., Cagdas D., Hosnut F.O., RA Dogu F., Ikinciogullari A., Rao V.K., Kainulainen L., Beziat V., RA Bustamante J., Vilarinho S., Lifton R.P., Boisson B., Abel L., RA Bogunovic D., Marr N., Notarangelo L.D., Tangye S.G., Honjo T., Gros P., RA Boisson-Dupuis S., Casanova J.L.; RT "Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a RT child."; RL Nat. Med. 27:1646-1654(2021). RN [19] RP FUNCTION, DEUBIQUITINATION BY USP5, AND PHOSPHORYLATION AT THR-234. RX PubMed=37208329; DOI=10.1038/s41467-023-38605-3; RA Xiao X., Shi J., He C., Bu X., Sun Y., Gao M., Xiang B., Xiong W., Dai P., RA Mao Q., Xing X., Yao Y., Yu H., Xu G., Li S., Ren Y., Chen B., Jiang C., RA Meng G., Lee Y.R., Wei W., Freeman G.J., Xie C., Zhang J.; RT "ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate RT tumor immunotherapy."; RL Nat. Commun. 14:2859-2859(2023). RN [20] {ECO:0007744|PDB:2M2D} RP STRUCTURE BY NMR OF 34-150, AND DISULFIDE BOND. RX PubMed=23417675; DOI=10.1074/jbc.m112.448126; RA Cheng X., Veverka V., Radhakrishnan A., Waters L.C., Muskett F.W., RA Morgan S.H., Huo J., Yu C., Evans E.J., Leslie A.J., Griffiths M., RA Stubberfield C., Griffin R., Henry A.J., Jansson A., Ladbury J.E., RA Ikemizu S., Carr M.D., Davis S.J.; RT "Structure and interactions of the human programmed cell death 1 RT receptor."; RL J. Biol. Chem. 288:11771-11785(2013). RN [21] {ECO:0007744|PDB:4ZQK} RP X-RAY CRYSTALLOGRAPHY (2.45 ANGSTROMS) OF 33-150 IN COMPLEX WITH CD274, RP FUNCTION, AND DISULFIDE BOND. RX PubMed=26602187; DOI=10.1016/j.str.2015.09.010; RA Zak K.M., Kitel R., Przetocka S., Golik P., Guzik K., Musielak B., RA Domling A., Dubin G., Holak T.A.; RT "Structure of the complex of human programmed death 1, PD-1, and its ligand RT PD-L1."; RL Structure 23:2341-2348(2015). RN [22] {ECO:0007744|PDB:5B8C} RP X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) OF 32-160 IN COMPLEX WITH RP PEMBROLIZUMAB, ACTIVITY REGULATION, AND DISULFIDE BOND. RX PubMed=27734966; DOI=10.1038/srep35297; RA Horita S., Nomura Y., Sato Y., Shimamura T., Iwata S., Nomura N.; RT "High-resolution crystal structure of the therapeutic antibody RT pembrolizumab bound to the human PD-1."; RL Sci. Rep. 6:35297-35297(2016). RN [23] {ECO:0007744|PDB:5IUS} RP X-RAY CRYSTALLOGRAPHY (2.89 ANGSTROMS) OF 26-146. RX PubMed=27618663; DOI=10.1016/j.str.2016.06.026; RA Pascolutti R., Sun X., Kao J., Maute R.L., Ring A.M., Bowman G.R., RA Kruse A.C.; RT "Structure and Dynamics of PD-L1 and an Ultra-High-Affinity PD-1 Receptor RT Mutant."; RL Structure 24:1719-1728(2016). RN [24] {ECO:0007744|PDB:5JXE} RP X-RAY CRYSTALLOGRAPHY (2.90 ANGSTROMS) OF 33-146 IN COMPLEX WITH RP PEMBROLIZUMAB, ACTIVITY REGULATION, AND DISULFIDE BOND. RX PubMed=27325296; DOI=10.1038/cr.2016.77; RA Na Z., Yeo S.P., Bharath S.R., Bowler M.W., Balikci E., Wang C.I., Song H.; RT "Structural basis for blocking PD-1-mediated immune suppression by RT therapeutic antibody pembrolizumab."; RL Cell Res. 27:147-150(2017). RN [25] {ECO:0007744|PDB:5WT9} RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 1-167 IN COMPLEX WITH NIVOLUMAB, RP GLYCOSYLATION AT ASN-49; ASN-58; ASN-74 AND ASN-116, AND MUTAGENESIS OF RP ASN-49; ASN-58; ASN-74 AND ASN-116. RX PubMed=28165004; DOI=10.1038/ncomms14369; RA Tan S., Zhang H., Chai Y., Song H., Tong Z., Wang Q., Qi J., Wong G., RA Zhu X., Liu W.J., Gao S., Wang Z., Shi Y., Yang F., Gao G.F., Yan J.; RT "An unexpected N-terminal loop in PD-1 dominates binding by nivolumab."; RL Nat. Commun. 8:14369-14369(2017). 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:21276005, PubMed:31754127, PubMed:32184441, PubMed:37208329). CC Delivers inhibitory signals upon binding to ligands CD274/PDCD1L1 and CC CD273/PDCD1LG2 (PubMed:21276005, PubMed:26602187). Following T-cell CC receptor (TCR) engagement, PDCD1 associates with TCR-CD3 in the CC immunological synapse and directly inhibits T-cell activation CC (PubMed:32184441). 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:32184441). {ECO:0000269|PubMed:21276005, CC ECO:0000269|PubMed:26602187, ECO:0000269|PubMed:31754127, CC ECO:0000269|PubMed:32184441, ECO:0000269|PubMed:37208329}. CC -!- FUNCTION: The PDCD1-mediated inhibitory pathway is exploited by tumors CC to attenuate anti-tumor immunity and escape destruction by the immune CC system, thereby facilitating tumor survival (PubMed:28951311). The CC interaction with CD274/PDCD1L1 inhibits cytotoxic T lymphocytes (CTLs) CC effector function (PubMed:28951311). The blockage of the PDCD1-mediated CC pathway results in the reversal of the exhausted T-cell phenotype and CC the normalization of the anti-tumor response, providing a rationale for CC cancer immunotherapy (PubMed:22658127, PubMed:25034862, CC PubMed:25399552). {ECO:0000269|PubMed:22658127, CC ECO:0000269|PubMed:25034862, ECO:0000269|PubMed:25399552, CC ECO:0000303|PubMed:28951311}. CC -!- ACTIVITY REGULATION: Inhibited by pembrolizumab (also named MK-3475 or CC lambrolizumab), a monoclonal antibody that prevents the interaction CC with CD274/PDCD1L1 (PubMed:27325296, PubMed:27734966). Inhibited by CC nivolumab (also named ONO-4538, BMS-936558 or Opdivo), a monoclonal CC antibody that prevents the interaction with CD274/PDCD1L1 CC (PubMed:28165004). The interaction with nivolumab is not dependent on CC glycosylation and depends on a loop at the N-terminus (N-terminal loop, CC corresponding to residues 25-34) (PubMed:28165004). Targeting the CC interaction between PDCD1 and CD274/PDCD1L1 with pembrolizumab and CC nivolumab antibodies has demonstrated great promise as a strategy for CC controlling and eradicating cancer (PubMed:22658127, PubMed:25034862, CC PubMed:25399552). Pembrolizumab and nivolumab are used for treatment of CC patients with advanced melanoma (PubMed:25034862, PubMed:25399552). CC These antibodies are also effective against other cancers, such as non- CC small cell lung cancer, renal cell carcinoma, bladder cancer and CC Hodgkin's lymphoma (PubMed:25034862). {ECO:0000269|PubMed:22658127, CC ECO:0000269|PubMed:25034862, ECO:0000269|PubMed:25399552, CC ECO:0000269|PubMed:27325296, ECO:0000269|PubMed:27734966, CC ECO:0000269|PubMed:28165004}. CC -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:26602187}. CC -!- INTERACTION: CC Q15116; Q9NZQ7: CD274; NbExp=20; IntAct=EBI-4314328, EBI-4314282; CC Q15116; Q9NZQ7-1: CD274; NbExp=2; IntAct=EBI-4314328, EBI-15686469; CC Q15116; Q9BQ51: PDCD1LG2; NbExp=17; IntAct=EBI-4314328, EBI-16427978; CC Q15116; Q06124: PTPN11; NbExp=3; IntAct=EBI-4314328, EBI-297779; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:30487606, CC ECO:0000269|PubMed:31754127}; Single-pass type I membrane protein. CC -!- DEVELOPMENTAL STAGE: Induced at programmed cell death. CC {ECO:0000269|PubMed:7851902}. CC -!- PTM: Ubiquitinated at Lys-233 by the SCF(FBXO38) complex, leading to CC its proteasomal degradation (PubMed:30487606). Ubiquitinated via 'Lys- CC 48'-linked polyubiquitin chains (PubMed:30487606). Deubiquitinated and CC thus stabilized by USP5 (PubMed:37208329). CC {ECO:0000269|PubMed:30487606, ECO:0000269|PubMed:37208329}. CC -!- PTM: Tyrosine phosphorylated at Tyr-223 (within ITIM motif) and Tyr-248 CC (ITSM motif) upon ligand binding (PubMed:31754127, PubMed:32184441). CC Phosphorylation at Tyr-248 by FYN promotes the recruitment of the CC protein tyrosine phosphatase PTPN11/SHP-2 that mediates CC dephosphorylation of key TCR proximal signaling molecules, such as CC ZAP70, PRKCQ/PKCtheta and CD247/CD3zeta (PubMed:32184441). CC Phosphorylation at Thr-234 promotes the recruitment of the CC deubiquitinase USP5 (PubMed:37208329). {ECO:0000269|PubMed:31754127, CC ECO:0000269|PubMed:32184441, ECO:0000269|PubMed:37208329}. CC -!- PTM: N-glycosylation at Asn-58 contains at least two N- CC acetylglucosamine units and one fucose (PubMed:28165004). N- CC glycosylation does not affect binding to nivolumab drug CC (PubMed:28165004). {ECO:0000269|PubMed:28165004}. CC -!- DISEASE: Autoimmune disease, multisystem, infantile-onset, 4 (ADMIO4) CC [MIM:621004]: An autosomal recessive immunologic disorder characterized CC by lymphoproliferative autoimmunity and onset of various autoimmune CC diseases in early childhood. Death from autoimmune pneumonitis may CC occur. {ECO:0000269|PubMed:34183838}. Note=The disease may be caused by CC variants affecting the gene represented in this entry. PDCD1 deficiency CC due to a homozygous frameshift mutation has been detected in a patient CC with severe tuberculosis and autoimmunity. The patient had depletion CC and dysfunction of multiple T and NK lymphocyte subsets and impaired CC gamma-IFN production. {ECO:0000269|PubMed:34183838}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; L27440; AAC41700.1; -; Genomic_DNA. DR EMBL; U64863; AAC51773.1; -; mRNA. DR EMBL; AF363458; AAN64003.1; -; Genomic_DNA. DR EMBL; AY238517; AAO63583.1; -; mRNA. DR EMBL; EF064716; ABK41899.1; -; Genomic_DNA. DR EMBL; AK313848; BAG36577.1; -; mRNA. DR EMBL; CH471063; EAW71298.1; -; Genomic_DNA. DR EMBL; BC074740; AAH74740.1; -; mRNA. DR CCDS; CCDS33428.1; -. DR PIR; A55737; A55737. DR RefSeq; NP_005009.2; NM_005018.3. DR PDB; 2M2D; NMR; -; A=34-150. DR PDB; 3RRQ; X-ray; 2.10 A; A=32-160. DR PDB; 4ZQK; X-ray; 2.45 A; B=33-150. DR PDB; 5B8C; X-ray; 2.15 A; C/F/I/L=32-160. DR PDB; 5GGR; X-ray; 3.30 A; Y/Z=26-150. DR PDB; 5GGS; X-ray; 2.00 A; Y/Z=26-148. DR PDB; 5IUS; X-ray; 2.89 A; A/B=26-146. DR PDB; 5JXE; X-ray; 2.90 A; A/B=33-146. DR PDB; 5WT9; X-ray; 2.40 A; G=1-167. DR PDB; 6HIG; X-ray; 2.20 A; B=33-150. DR PDB; 6J14; X-ray; 1.40 A; G=33-147. DR PDB; 6J15; X-ray; 2.60 A; C/D=32-147. DR PDB; 6JBT; X-ray; 2.47 A; F=21-170. DR PDB; 6JJP; X-ray; 2.90 A; C/F=21-167. DR PDB; 6K0Y; X-ray; 1.70 A; C=25-167. DR PDB; 6R5G; NMR; -; B=244-254. DR PDB; 6ROY; X-ray; 2.10 A; C/D=219-229. DR PDB; 6ROZ; X-ray; 2.89 A; B/D=244-254. DR PDB; 6UMT; X-ray; 1.99 A; A=33-150. DR PDB; 6UMU; X-ray; 1.18 A; A=33-150. DR PDB; 6UMV; X-ray; 1.42 A; A=33-150. DR PDB; 6XKR; X-ray; 2.59 A; P=32-160. DR PDB; 7BXA; X-ray; 3.32 A; A/P=29-150. DR PDB; 7CGW; X-ray; 3.20 A; C/P=25-169. DR PDB; 7CU5; X-ray; 2.81 A; E/Q=30-147. DR PDB; 7E9B; X-ray; 1.78 A; C=32-146. DR PDB; 7VUX; X-ray; 1.64 A; A=32-160. DR PDB; 7WSL; X-ray; 1.53 A; D=29-150. DR PDB; 7WVM; X-ray; 3.40 A; E/F=31-147. DR PDB; 8AS0; X-ray; 3.50 A; A/F/I/L/O/R/X/Y=24-170. DR PDB; 8EQ6; X-ray; 1.65 A; A=25-148. DR PDB; 8GY5; X-ray; 1.98 A; P/Q=26-150. DR PDB; 8U31; X-ray; 2.73 A; A=25-146. DR PDB; 8U32; X-ray; 2.51 A; A/D=25-146. DR PDB; 9EHT; X-ray; 1.54 A; F/J=26-150. DR PDB; 9HK1; X-ray; 2.03 A; A/B=25-148. DR PDB; 9Q8L; X-ray; 1.85 A; A=24-170. DR AlphaFoldDB; Q15116; -. DR BMRB; Q15116; -. DR MDposit; Q15116; -. DR SMR; Q15116; -. DR BioGRID; 111160; 133. DR CORUM; Q15116; -. DR DIP; DIP-44126N; -. DR FunCoup; Q15116; 872. DR IntAct; Q15116; 73. DR MINT; Q15116; -. DR NDEx; IQUERY-CP-PDCD1; 7 NDEx IQuery Curated Pathways. DR STRING; 9606.ENSP00000335062; -. DR BindingDB; Q15116; -. DR ChEMBL; CHEMBL3307223; -. DR DrugBank; DB15767; AMP-224. DR DrugBank; DB15771; AUNP-12. DR DrugBank; DB16668; Budigalimab. DR DrugBank; DB14776; Camrelizumab. DR DrugBank; DB14707; Cemiplimab. DR DrugBank; DB05916; CT-011. DR DrugBank; DB15627; Dostarlimab. DR DrugBank; DB16417; Geptanolimab. DR DrugBank; DB18931; Ivonescimab. DR DrugBank; DB15768; MEDI0680. DR DrugBank; DB09035; Nivolumab. DR DrugBank; DB09037; Pembrolizumab. DR DrugBank; DB16747; Penpulimab. DR DrugBank; DB16740; Prolgolimab. DR DrugBank; DB15766; Retifanlimab. DR DrugBank; DB17451; Serplulimab. DR DrugBank; DB15765; Sintilimab. DR DrugBank; DB14892; Spartalizumab. DR DrugBank; DB14922; Tislelizumab. DR DrugBank; DB15043; Toripalimab. DR DrugCentral; Q15116; -. DR GuidetoPHARMACOLOGY; 2760; -. DR TCDB; 8.A.17.4.1; the na(+) channel auxiliary subunit Beta1-Beta4 (sca-Beta) family. DR GlyCosmos; Q15116; 4 sites, No reported glycans. DR GlyGen; Q15116; 5 sites, 2 N-linked glycans (2 sites). DR iPTMnet; Q15116; -. DR PhosphoSitePlus; Q15116; -. DR BioMuta; PDCD1; -. DR DMDM; 145559515; -. DR MassIVE; Q15116; -. DR PaxDb; 9606-ENSP00000335062; -. DR PeptideAtlas; Q15116; -. DR ProteomicsDB; 60443; -. DR ABCD; Q15116; 147 sequenced antibodies. DR Antibodypedia; 20331; 3435 antibodies from 58 providers. DR CPTC; Q15116; 1 antibody. DR DNASU; 5133; -. DR Ensembl; ENST00000334409.10; ENSP00000335062.5; ENSG00000188389.13. DR Ensembl; ENST00000618185.3; ENSP00000480684.1; ENSG00000276977.3. DR GeneID; 5133; -. DR KEGG; hsa:5133; -. DR MANE-Select; ENST00000334409.10; ENSP00000335062.5; NM_005018.3; NP_005009.2. DR UCSC; uc002wcq.5; human. DR AGR; HGNC:8760; -. DR ClinPGx; PA33110; -. DR CTD; 5133; -. DR DisGeNET; 5133; -. DR GeneCards; PDCD1; -. DR HGNC; HGNC:8760; PDCD1. DR HPA; ENSG00000188389; Tissue enhanced (heart muscle, lymphoid tissue). DR MalaCards; PDCD1; -. DR MIM; 600244; gene. DR MIM; 621004; phenotype. DR OpenTargets; ENSG00000188389; -. DR Orphanet; 536; Systemic lupus erythematosus. DR VEuPathDB; HostDB:ENSG00000188389; -. DR eggNOG; ENOG502SUIW; Eukaryota. DR GeneTree; ENSGT00390000013662; -. DR HOGENOM; CLU_1075828_0_0_1; -. DR InParanoid; Q15116; -. DR OMA; CVHTEYA; -. DR OrthoDB; 9940233at2759; -. DR PAN-GO; Q15116; 2 GO annotations based on evolutionary models. DR PhylomeDB; Q15116; -. DR PathwayCommons; Q15116; -. DR Reactome; R-HSA-389948; Co-inhibition by PD-1. DR Reactome; R-HSA-9679191; Potential therapeutics for SARS. DR Reactome; R-HSA-9931295; PD-L1(CD274) glycosylation and translocation to plasma membrane. DR SignaLink; Q15116; -. DR SIGNOR; Q15116; -. DR Agora; ENSG00000188389; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 5133; 11 hits in 1153 CRISPR screens. DR ChiTaRS; PDCD1; human. DR EvolutionaryTrace; Q15116; -. DR GeneWiki; Programmed_cell_death_1; -. DR GenomeRNAi; 5133; -. DR Pharos; Q15116; Tclin. DR PRO; PR:Q15116; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; Q15116; protein. DR Bgee; ENSG00000188389; Expressed in lymph node and 85 other cell types or tissues. DR ExpressionAtlas; Q15116; baseline and differential. DR GO; GO:0009897; C:external side of plasma membrane; IBA:GO_Central. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0038023; F:signaling receptor activity; IDA:UniProt. DR GO; GO:0004888; F:transmembrane signaling receptor activity; IDA:UniProtKB. DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc. DR GO; GO:0006959; P:humoral immune response; TAS:ProtInc. DR GO; GO:0050777; P:negative regulation of immune response; ISS:UniProtKB. DR GO; GO:0050728; P:negative regulation of inflammatory response; IC:UniProt. DR GO; GO:0050868; P:negative regulation of T cell activation; IDA:UniProtKB. DR GO; GO:0002841; P:negative regulation of T cell mediated immune response to tumor cell; IDA:UniProtKB. DR GO; GO:0050860; P:negative regulation of T cell receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0050776; P:regulation of immune response; IBA:GO_Central. DR CDD; cd16088; IgV_PD1; 1. DR FunFam; 2.60.40.10:FF:001952; Programmed cell death protein 1; 1. DR Gene3D; 2.60.40.10; Immunoglobulins; 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; PROGRAMMED CELL DEATH PROTEIN 1; 1. DR PANTHER; PTHR15264:SF2; PROGRAMMED CELL DEATH PROTEIN 1; 1. DR Pfam; PF07686; V-set; 1. DR SMART; SM00409; IG; 1. DR SMART; SM00406; IGv; 1. DR SUPFAM; SSF48726; Immunoglobulin; 1. DR PROSITE; PS50835; IG_LIKE; 1. DR PDBsum; 2M2D; -. DR PDBsum; 3RRQ; -. DR PDBsum; 4ZQK; -. DR PDBsum; 5B8C; -. DR PDBsum; 5GGR; -. DR PDBsum; 5GGS; -. DR PDBsum; 5IUS; -. DR PDBsum; 5JXE; -. DR PDBsum; 5WT9; -. DR PDBsum; 6HIG; -. DR PDBsum; 6J14; -. DR PDBsum; 6J15; -. DR PDBsum; 6JBT; -. DR PDBsum; 6JJP; -. DR PDBsum; 6K0Y; -. DR PDBsum; 6R5G; -. DR PDBsum; 6ROY; -. DR PDBsum; 6ROZ; -. DR PDBsum; 6UMT; -. DR PDBsum; 6UMU; -. DR PDBsum; 6UMV; -. DR PDBsum; 6XKR; -. DR PDBsum; 7BXA; -. DR PDBsum; 7CGW; -. DR PDBsum; 7CU5; -. DR PDBsum; 7E9B; -. DR PDBsum; 7VUX; -. DR PDBsum; 7WSL; -. DR PDBsum; 7WVM; -. DR PDBsum; 8AS0; -. DR PDBsum; 8EQ6; -. DR PDBsum; 8GY5; -. DR PDBsum; 8U31; -. DR PDBsum; 8U32; -. DR PDBsum; 9EHT; -. DR PDBsum; 9HK1; -. DR PDBsum; 9Q8L; -. 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; Proteomics identification; Reference proteome; Signal; KW Transmembrane; 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_0000014892" FT TOPO_DOM 25..170 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 171..191 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 192..288 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 35..145 FT /note="Ig-like V-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114" FT REGION 25..34 FT /note="Nivolumab binding" FT /evidence="ECO:0000269|PubMed:28165004, FT ECO:0007744|PDB:5WT9" FT REGION 70..77 FT /note="Interaction with CD274/PDCD1L1" FT /evidence="ECO:0000269|PubMed:26602187" FT REGION 74..99 FT /note="Pembrolizumab binding" FT /evidence="ECO:0000269|PubMed:27325296, FT ECO:0000269|PubMed:27734966, ECO:0007744|PDB:5B8C, FT ECO:0007744|PDB:5JXE" FT REGION 254..288 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 221..226 FT /note="ITIM motif" FT /evidence="ECO:0000250|UniProtKB:Q02242" FT MOTIF 247..251 FT /note="ITSM motif" FT /evidence="ECO:0000250|UniProtKB:Q02242" FT COMPBIAS 278..288 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 223 FT /note="Phosphotyrosine" FT /evidence="ECO:0000269|PubMed:32184441" FT MOD_RES 234 FT /note="Phosphothreonine; by MAPK3" FT /evidence="ECO:0000269|PubMed:37208329" FT MOD_RES 248 FT /note="Phosphotyrosine; by FYN" FT /evidence="ECO:0000269|PubMed:31754127, FT ECO:0000269|PubMed:32184441" FT CARBOHYD 49 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000305|PubMed:28165004" FT CARBOHYD 58 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:28165004, FT ECO:0007744|PDB:5WT9" FT CARBOHYD 74 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000305|PubMed:28165004" FT CARBOHYD 116 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000305|PubMed:28165004" FT DISULFID 54..123 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114, FT ECO:0000269|PubMed:23417675, ECO:0000269|PubMed:26602187, FT ECO:0000269|PubMed:27325296, ECO:0000269|PubMed:27734966, FT ECO:0007744|PDB:2M2D, ECO:0007744|PDB:4ZQK, FT ECO:0007744|PDB:5B8C, ECO:0007744|PDB:5JXE" FT CROSSLNK 233 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:30487606" FT VARIANT 215 FT /note="A -> V (in dbSNP:rs2227982)" FT /id="VAR_031685" FT MUTAGEN 49 FT /note="N->A: Decreased N-glycosylation without affecting FT binding to binding to nivolumab drug." FT /evidence="ECO:0000269|PubMed:28165004" FT MUTAGEN 58 FT /note="N->A: Decreased N-glycosylation without affecting FT binding to binding to nivolumab drug." FT /evidence="ECO:0000269|PubMed:28165004" FT MUTAGEN 74 FT /note="N->A: Decreased N-glycosylation without affecting FT binding to binding to nivolumab drug." FT /evidence="ECO:0000269|PubMed:28165004" FT MUTAGEN 116 FT /note="N->A: Decreased N-glycosylation without affecting FT binding to binding to nivolumab drug." FT /evidence="ECO:0000269|PubMed:28165004" FT MUTAGEN 210 FT /note="K->R: Does not affect ubiquitination by the FT SCF(FBXO38) complex." FT /evidence="ECO:0000269|PubMed:30487606" FT MUTAGEN 223 FT /note="Y->F: Reduced tyrosine phosphorylation without FT affecting ability to mediate recruitment of PTPN11/SHP-2." FT /evidence="ECO:0000269|PubMed:32184441" FT MUTAGEN 233 FT /note="K->R: Abolishes ubiquitination by the SCF(FBXO38) FT complex." FT /evidence="ECO:0000269|PubMed:30487606" 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:32184441" FT CONFLICT 38 FT /note="S -> F (in Ref. 2; AAC51773)" FT /evidence="ECO:0000305" FT CONFLICT 162 FT /note="P -> S (in Ref. 1; AAC41700)" FT /evidence="ECO:0000305" FT STRAND 27..29 FT /evidence="ECO:0007829|PDB:5WT9" FT HELIX 33..35 FT /evidence="ECO:0007829|PDB:6UMU" FT STRAND 36..38 FT /evidence="ECO:0007829|PDB:6UMU" FT STRAND 40..45 FT /evidence="ECO:0007829|PDB:6UMU" FT STRAND 46..48 FT /evidence="ECO:0007829|PDB:8U31" FT STRAND 50..55 FT /evidence="ECO:0007829|PDB:6UMU" FT STRAND 59..61 FT /evidence="ECO:0007829|PDB:7WSL" FT STRAND 63..69 FT /evidence="ECO:0007829|PDB:6UMU" FT STRAND 72..74 FT /evidence="ECO:0007829|PDB:4ZQK" FT STRAND 77..83 FT /evidence="ECO:0007829|PDB:6UMU" FT HELIX 84..86 FT /evidence="ECO:0007829|PDB:6K0Y" FT STRAND 87..90 FT /evidence="ECO:0007829|PDB:7CGW" FT STRAND 94..99 FT /evidence="ECO:0007829|PDB:6UMU" FT STRAND 103..112 FT /evidence="ECO:0007829|PDB:6UMU" FT HELIX 115..117 FT /evidence="ECO:0007829|PDB:6UMU" FT STRAND 119..127 FT /evidence="ECO:0007829|PDB:6UMU" FT STRAND 129..131 FT /evidence="ECO:0007829|PDB:6UMU" FT STRAND 133..136 FT /evidence="ECO:0007829|PDB:6UMU" FT HELIX 137..139 FT /evidence="ECO:0007829|PDB:6UMU" FT STRAND 140..145 FT /evidence="ECO:0007829|PDB:6UMU" FT HELIX 146..151 FT /evidence="ECO:0007829|PDB:7VUX" SQ SEQUENCE 288 AA; 31647 MW; A5210FD40C304FB7 CRC64; MQIPQAPWPV VWAVLQLGWR PGWFLDSPDR PWNPPTFSPA LLVVTEGDNA TFTCSFSNTS ESFVLNWYRM SPSNQTDKLA AFPEDRSQPG QDCRFRVTQL PNGRDFHMSV VRARRNDSGT YLCGAISLAP KAQIKESLRA ELRVTERRAE VPTAHPSPSP RPAGQFQTLV VGVVGGLLGS LVLLVWVLAV ICSRAARGTI GARRTGQPLK EDPSAVPVFS VDYGELDFQW REKTPEPPVP CVPEQTEYAT IVFPSGMGTS SPARRGSADG PRSAQPLRPE DGHCSWPL //