ID MD2L1_HUMAN Reviewed; 205 AA. AC Q13257; Q53F56; Q548X9; Q6IRW7; Q8IZX3; DT 11-JAN-2001, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 27-MAR-2024, entry version 219. DE RecName: Full=Mitotic spindle assembly checkpoint protein MAD2A; DE Short=HsMAD2; DE AltName: Full=Mitotic arrest deficient 2-like protein 1; DE Short=MAD2-like protein 1; GN Name=MAD2L1; Synonyms=MAD2; 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 [MRNA] (ISOFORM 1). RX PubMed=8824189; DOI=10.1126/science.274.5285.246; RA Li Y., Benezra R.; RT "Identification of a human mitotic checkpoint gene: hsMAD2."; RL Science 274:246-248(1996). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=11390010; DOI=10.1016/s0169-5002(00)00223-3; RA Gemma A., Hosoya Y., Seike M., Uematsu K., Kurimoto F., Hibino S., RA Yoshimura A., Shibuya M., Kudoh S., Emi M.; RT "Genomic structure of the human MAD2 gene and mutation analysis in human RT lung and breast cancers."; RL Lung Cancer 32:289-295(2001). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Jin D.-Y., Jeang K.-T.; RL Submitted (JUL-1995) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Brain; RA Klebert S., Barnikol-Watanabe S., Kratzin H.D., Hilschmann N.; RL Submitted (OCT-1997) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Nobori T.; RT "Complete human MAD2 gene."; RL Submitted (FEB-2001) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RA Yin F., Fan D.M.; RT "Identifying a new variant of MAD2L1."; RL Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Lung; 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] (ISOFORM 1). RC TISSUE=Testis; RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.; RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.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 (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Bone marrow, and Muscle; 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 [12] RP PROTEIN SEQUENCE OF 2-7; 36-45; 123-129 AND 193-205, CLEAVAGE OF INITIATOR RP METHIONINE, ACETYLATION AT ALA-2, AND IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Hepatoma; RA Bienvenut W.V., Dhillon A.S., Kolch W.; RL Submitted (FEB-2008) to UniProtKB. RN [13] RP INTERACTION WITH CDC20. RX PubMed=9637688; DOI=10.1101/gad.12.12.1871; RA Fang G., Yu H., Kirschner M.W.; RT "The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary RT complex with the anaphase-promoting complex to control anaphase RT initiation."; RL Genes Dev. 12:1871-1883(1998). RN [14] RP INTERACTION WITH ADAM17. RX PubMed=10527948; DOI=10.1042/bj3430673; RA Nelson K.K., Schlondorff J., Blobel C.P.; RT "Evidence for an interaction of the metalloprotease-disintegrin tumour RT necrosis factor alpha convertase (TACE) with mitotic arrest deficient 2 RT (MAD2), and of the metalloprotease-disintegrin MDC9 with a novel MAD2- RT related protein, MAD2-beta."; RL Biochem. J. 343:673-680(1999). RN [15] RP INTERACTION WITH MAD2L1BP. RX PubMed=12456649; DOI=10.1093/emboj/cdf659; RA Habu T., Kim S.H., Weinstein J., Matsumoto T.; RT "Identification of a MAD2-binding protein, CMT2, and its role in mitosis."; RL EMBO J. 21:6419-6428(2002). RN [16] RP PHOSPHORYLATION AT SER-170; SER-178 AND SER-195, INTERACTION WITH MAD1L1 RP AND CDC20, AND MUTAGENESIS OF SER-170; SER-178 AND SER-195. RX PubMed=12574116; DOI=10.1093/emboj/cdg071; RA Wassmann K., Liberal V., Benezra R.; RT "Mad2 phosphorylation regulates its association with Mad1 and the APC/C."; RL EMBO J. 22:797-806(2003). RN [17] RP SUBCELLULAR LOCATION. RX PubMed=14978040; DOI=10.1074/jbc.m314205200; RA Lou Y., Yao J., Zereshki A., Dou Z., Ahmed K., Wang H., Hu J., Wang Y., RA Yao X.; RT "NEK2A interacts with MAD1 and possibly functions as a novel integrator of RT the spindle checkpoint signaling."; RL J. Biol. Chem. 279:20049-20057(2004). RN [18] RP SUBCELLULAR LOCATION. RX PubMed=15020684; DOI=10.1242/jcs.01006; RA Johnson V.L., Scott M.I., Holt S.V., Hussein D., Taylor S.S.; RT "Bub1 is required for kinetochore localization of BubR1, Cenp-E, Cenp-F and RT Mad2, and chromosome congression."; RL J. Cell Sci. 117:1577-1589(2004). RN [19] RP SUBCELLULAR LOCATION, AND INTERACTION WITH UBD. RX PubMed=16495226; DOI=10.1074/jbc.m507218200; RA Ren J., Kan A., Leong S.H., Ooi L.L.P.J., Jeang K.-T., Chong S.S., RA Kon O.L., Lee C.G.L.; RT "FAT10 plays a role in the regulation of chromosomal stability."; RL J. Biol. Chem. 281:11413-11421(2006). RN [20] RP INTERACTION WITH HSF1. RX PubMed=18794143; DOI=10.1158/0008-5472.can-08-0129; RA Lee Y.J., Kim E.H., Lee J.S., Jeoung D., Bae S., Kwon S.H., Lee Y.S.; RT "HSF1 as a mitotic regulator: phosphorylation of HSF1 by Plk1 is essential RT for mitotic progression."; RL Cancer Res. 68:7550-7560(2008). RN [21] RP INTERACTION WITH MAD1L1, AND SUBCELLULAR LOCATION. RX PubMed=19010891; DOI=10.1158/0008-5472.can-08-2600; RA Sze K.M., Ching Y.P., Jin D.Y., Ng I.O.; RT "Role of a novel splice variant of mitotic arrest deficient 1 (MAD1), RT MAD1beta, in mitotic checkpoint control in liver cancer."; RL Cancer Res. 68:9194-9201(2008). RN [22] RP INTERACTION WITH TPR; MAD1L1 AND CDC20, AND SUBCELLULAR LOCATION. RX PubMed=18981471; DOI=10.1101/gad.1677208; RA Lee S.H., Sterling H., Burlingame A., McCormick F.; RT "Tpr directly binds to Mad1 and Mad2 and is important for the Mad1-Mad2- RT mediated mitotic spindle checkpoint."; RL Genes Dev. 22:2926-2931(2008). RN [23] RP SUBCELLULAR LOCATION. RX PubMed=18712773; DOI=10.1002/jcb.21879; RA Ho C.-Y., Wong C.-H., Li H.-Y.; RT "Perturbation of the chromosomal binding of RCC1, Mad2 and survivin causes RT spindle assembly defects and mitotic catastrophe."; RL J. Cell. Biochem. 105:835-846(2008). RN [24] RP REVIEW. RX PubMed=19029339; DOI=10.1083/jcb.200808122; RA Skinner J.J., Wood S., Shorter J., Englander S.W., Black B.E.; RT "The Mad2 partial unfolding model: regulating mitosis through Mad2 RT conformational switching."; RL J. Cell Biol. 183:761-768(2008). RN [25] RP SUBCELLULAR LOCATION, PHOSPHORYLATION, AND INTERACTION WITH NEK2. RX PubMed=20034488; DOI=10.1016/j.yexmp.2009.12.004; RA Liu Q., Hirohashi Y., Du X., Greene M.I., Wang Q.; RT "Nek2 targets the mitotic checkpoint proteins Mad2 and Cdc20: a mechanism RT for aneuploidy in cancer."; RL Exp. Mol. Pathol. 88:225-233(2010). RN [26] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [27] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-6; SER-130; SER-185 AND RP SER-195, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [28] RP INTERACTION WITH UBD. RX PubMed=25422469; DOI=10.1073/pnas.1403383111; RA Theng S.S., Wang W., Mah W.C., Chan C., Zhuo J., Gao Y., Qin H., Lim L., RA Chong S.S., Song J., Lee C.G.; RT "Disruption of FAT10-MAD2 binding inhibits tumor progression."; RL Proc. Natl. Acad. Sci. U.S.A. 111:E5282-E5291(2014). RN [29] RP FUNCTION, INTERACTION WITH MAD1L1; CDC20; BUB1B AND TTK, AND MUTAGENESIS OF RP LEU-13 AND SER-195. RX PubMed=29162720; DOI=10.1074/jbc.ra117.000555; RA Ji W., Luo Y., Ahmad E., Liu S.T.; RT "Direct interactions of mitotic arrest deficient 1 (MAD1) domains with each RT other and MAD2 conformers are required for mitotic checkpoint signaling."; RL J. Biol. Chem. 293:484-496(2018). RN [30] RP STRUCTURE BY NMR OF 11-195, FUNCTION, DOMAIN, AND INTERACTION WITH CDC20. RX PubMed=10700282; DOI=10.1038/73338; RA Luo X., Fang G., Coldiron M., Lin Y., Yu H., Kirschner M.W., Wagner G.; RT "Structure of the Mad2 spindle assembly checkpoint protein and its RT interaction with Cdc20."; RL Nat. Struct. Biol. 7:224-229(2000). RN [31] RP X-RAY CRYSTALLOGRAPHY (2.05 ANGSTROMS) OF MUTANT ALA-133 IN COMPLEX WITH RP MAD1L1, SUBUNIT, DOMAIN, MUTAGENESIS OF ARG-133, AND INTERACTION WITH RP MAD1L1. RX PubMed=12006501; DOI=10.1093/emboj/21.10.2496; RA Sironi L., Mapelli M., Knapp S., De Antoni A., Jeang K.-T., Musacchio A.; RT "Crystal structure of the tetrameric Mad1-Mad2 core complex: implications RT of a 'safety belt' binding mechanism for the spindle checkpoint."; RL EMBO J. 21:2496-2506(2002). RN [32] RP STRUCTURE BY NMR OF 11-205 IN COMPLEX WITH PEPTIDE LIGAND, DOMAIN, RP SUBCELLULAR LOCATION, FUNCTION, AND INTERACTION WITH CDC20 AND MAD1L1. RX PubMed=11804586; DOI=10.1016/s1097-2765(01)00435-x; RA Luo X., Tang Z., Rizo J., Yu H.; RT "The Mad2 spindle checkpoint protein undergoes similar major conformational RT changes upon binding to either Mad1 or Cdc20."; RL Mol. Cell 9:59-71(2002). RN [33] RP STRUCTURE BY NMR, DOMAIN, SUBUNIT, FUNCTION, INTERACTION WITH MAD1L1, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=15024386; DOI=10.1038/nsmb748; RA Luo X., Tang Z., Xia G., Wassmann K., Matsumoto T., Rizo J., Yu H.; RT "The Mad2 spindle checkpoint protein has two distinct natively folded RT states."; RL Nat. Struct. Mol. Biol. 11:338-345(2004). RN [34] RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF DIMER CONTAINING BOTH CONFORMERS, RP AND INTERACTION OF THE TWO MAD2L1 CONFORMERS. RX PubMed=18022367; DOI=10.1016/j.cell.2007.08.049; RA Mapelli M., Massimiliano L., Santaguida S., Musacchio A.; RT "The Mad2 conformational dimer: structure and implications for the spindle RT assembly checkpoint."; RL Cell 131:730-743(2007). RN [35] RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF COMPLEXES WITH MAD2L1BP, AND RP INTERACTION WITH MAD2L1BP. RX PubMed=18022368; DOI=10.1016/j.cell.2007.08.048; RA Yang M., Li B., Tomchick D.R., Machius M., Rizo J., Yu H., Luo X.; RT "p31comet blocks Mad2 activation through structural mimicry."; RL Cell 131:744-755(2007). RN [36] RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF HOMODIMER OF MUTANT ALA-13 IN THE RP CLOSED CONFORMATION, DOMAIN, SUBUNIT, AND MUTAGENESIS OF LEU-13; TRP-75; RP LEU-153; TYR-156; PHE-186; THR-188; HIS-191; VAL-197 AND TYR-199. RX PubMed=18318601; DOI=10.1371/journal.pbio.0060050; RA Yang M., Li B., Liu C.-J., Tomchick D.R., Machius M., Rizo J., Yu H., RA Luo X.; RT "Insights into Mad2 regulation in the spindle checkpoint revealed by the RT crystal structure of the symmetric Mad2 dimer."; RL PLoS Biol. 6:E50-E50(2008). CC -!- FUNCTION: Component of the spindle-assembly checkpoint that prevents CC the onset of anaphase until all chromosomes are properly aligned at the CC metaphase plate (PubMed:29162720, PubMed:15024386). In the closed CC conformation (C-MAD2) forms a heterotetrameric complex with MAD1L1 at CC unattached kinetochores during prometaphase, the complex recruits open CC conformation molecules of MAD2L1 (O-MAD2) and then promotes the CC conversion of O-MAD2 to C-MAD2 (PubMed:29162720). Required for the CC execution of the mitotic checkpoint which monitors the process of CC kinetochore-spindle attachment and inhibits the activity of the CC anaphase promoting complex by sequestering CDC20 until all chromosomes CC are aligned at the metaphase plate (PubMed:10700282, PubMed:11804586, CC PubMed:15024386). {ECO:0000269|PubMed:10700282, CC ECO:0000269|PubMed:11804586, ECO:0000269|PubMed:15024386, CC ECO:0000269|PubMed:29162720}. CC -!- SUBUNIT: Monomer and homodimer (PubMed:18022367, PubMed:18318601). CC Heterodimerizes with MAD2L1 in order to form a tetrameric MAD1L1-MAD2L1 CC core complex (PubMed:12574116, PubMed:18981471, PubMed:12006501, CC PubMed:15024386). In the closed and open conformation, interacts with CC MAD1L1 (PubMed:29162720). Formation of a heterotetrameric core complex CC containing two molecules each of MAD1L1 and of MAD2L1 promotes binding CC of another molecule of MAD2L1 to each MAD2L1, resulting in a CC heterohexamer (PubMed:12006501). Interacts with MAD2L1BP CC (PubMed:12456649, PubMed:18022368). Interacts with ADAM17/TACE CC (PubMed:10527948). Interacts with CDC20 (PubMed:9637688, CC PubMed:12574116, PubMed:18981471, PubMed:10700282). Dimeric MAD2L1 in CC the closed conformation interacts with CDC20 (PubMed:29162720). CC Monomeric MAD2L1 in the open conformation does not interact with CDC20 CC (PubMed:11804586). CDC20 competes with MAD1L1 for MAD2L1 binding CC (PubMed:11804586). In the closed conformation, interacts with BUB1B CC (PubMed:29162720). Interacts with TTK (PubMed:29162720). Interacts with CC TPR (PubMed:18981471). Binds to UBD (via ubiquitin-like 1 domain) CC during mitosis (PubMed:16495226, PubMed:25422469). Interacts with CC isoform 1 and isoform 2 of NEK2 (PubMed:20034488). Interacts with HSF1; CC this interaction occurs in mitosis (PubMed:18794143). Interacts with CC isoform 3 of MAD1L1; this interaction leads to the cytoplasmic CC sequestration of MAD2L1 (PubMed:19010891). CC {ECO:0000269|PubMed:10527948, ECO:0000269|PubMed:10700282, CC ECO:0000269|PubMed:11804586, ECO:0000269|PubMed:12006501, CC ECO:0000269|PubMed:12456649, ECO:0000269|PubMed:12574116, CC ECO:0000269|PubMed:15024386, ECO:0000269|PubMed:16495226, CC ECO:0000269|PubMed:18022367, ECO:0000269|PubMed:18022368, CC ECO:0000269|PubMed:18318601, ECO:0000269|PubMed:18794143, CC ECO:0000269|PubMed:18981471, ECO:0000269|PubMed:19010891, CC ECO:0000269|PubMed:20034488, ECO:0000269|PubMed:25422469, CC ECO:0000269|PubMed:29162720, ECO:0000269|PubMed:9637688}. CC -!- INTERACTION: CC Q13257; P78536: ADAM17; NbExp=3; IntAct=EBI-78203, EBI-78188; CC Q13257; O60566: BUB1B; NbExp=13; IntAct=EBI-78203, EBI-1001438; CC Q13257; Q12834: CDC20; NbExp=34; IntAct=EBI-78203, EBI-367462; CC Q13257; P30260: CDC27; NbExp=9; IntAct=EBI-78203, EBI-994813; CC Q13257; O75140-2: DEPDC5; NbExp=3; IntAct=EBI-78203, EBI-12366971; CC Q13257; Q7L775: EPM2AIP1; NbExp=3; IntAct=EBI-78203, EBI-6255981; CC Q13257; P06213-2: INSR; NbExp=3; IntAct=EBI-78203, EBI-9984921; CC Q13257; Q14145: KEAP1; NbExp=8; IntAct=EBI-78203, EBI-751001; CC Q13257; Q9Y6D9: MAD1L1; NbExp=39; IntAct=EBI-78203, EBI-742610; CC Q13257; Q13257: MAD2L1; NbExp=9; IntAct=EBI-78203, EBI-78203; CC Q13257; Q15013: MAD2L1BP; NbExp=18; IntAct=EBI-78203, EBI-712181; CC Q13257; O00560: SDCBP; NbExp=3; IntAct=EBI-78203, EBI-727004; CC Q13257; Q562F6: SGO2; NbExp=10; IntAct=EBI-78203, EBI-989213; CC Q13257; Q9Y3Q8: TSC22D4; NbExp=5; IntAct=EBI-78203, EBI-739485; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:19010891}. CC Chromosome, centromere, kinetochore. Cytoplasm CC {ECO:0000269|PubMed:19010891}. Cytoplasm, cytoskeleton, spindle pole. CC Note=Recruited by MAD1L1 to unattached kinetochores (Probable). CC Recruited to the nuclear pore complex by TPR during interphase. CC Recruited to kinetochores in late prometaphase after BUB1, CENPF, BUB1B CC and CENPE. Kinetochore association requires the presence of NEK2. CC Kinetochore association is repressed by UBD. Sequestered to the CC cytoplasm upon interaction with isoform 3 of MAD1L1 (PubMed:19010891). CC {ECO:0000269|PubMed:19010891, ECO:0000305}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q13257-1; Sequence=Displayed; CC Name=2; CC IsoId=Q13257-2; Sequence=VSP_047644, VSP_047645; CC -!- DOMAIN: The protein has two highly different native conformations, an CC inactive open conformation that cannot bind CDC20 and that predominates CC in cytosolic monomers, and an active closed conformation. The protein CC in the closed conformation preferentially dimerizes with another CC molecule in the open conformation, but can also form a dimer with a CC molecule in the closed conformation. Formation of a heterotetrameric CC core complex containing two molecules of MAD1L1 and of MAD2L1 in the CC closed conformation promotes binding of another molecule of MAD2L1 in CC the open conformation and the conversion of the open to the closed CC form, and thereby promotes interaction with CDC20. CC {ECO:0000269|PubMed:10700282, ECO:0000269|PubMed:11804586, CC ECO:0000269|PubMed:12006501, ECO:0000269|PubMed:15024386, CC ECO:0000269|PubMed:18318601}. CC -!- PTM: Phosphorylated on multiple serine residues. The level of CC phosphorylation varies during the cell cycle and is highest during CC mitosis. Phosphorylation abolishes interaction with MAD1L1 and reduces CC interaction with CDC20. Phosphorylated by NEK2. CC {ECO:0000269|PubMed:12574116, ECO:0000269|PubMed:20034488}. CC -!- SIMILARITY: Belongs to the MAD2 family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/304/MAD2L1"; 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; U65410; AAC50781.1; -; mRNA. DR EMBL; AF202273; AAK38174.1; -; Genomic_DNA. DR EMBL; AF202269; AAK38174.1; JOINED; Genomic_DNA. DR EMBL; AF202270; AAK38174.1; JOINED; Genomic_DNA. DR EMBL; AF202271; AAK38174.1; JOINED; Genomic_DNA. DR EMBL; AF202272; AAK38174.1; JOINED; Genomic_DNA. DR EMBL; U31278; AAC52060.1; -; mRNA. DR EMBL; AJ000186; CAA03943.1; -; mRNA. DR EMBL; AB056160; BAB63410.1; -; Genomic_DNA. DR EMBL; AF394735; AAN74648.1; -; mRNA. DR EMBL; AK298228; BAG60497.1; -; mRNA. DR EMBL; AK313827; BAG36562.1; -; mRNA. DR EMBL; AK223433; BAD97153.1; -; mRNA. DR EMBL; AC097173; AAY40945.1; -; Genomic_DNA. DR EMBL; CH471056; EAX05271.1; -; Genomic_DNA. DR EMBL; CH471056; EAX05273.1; -; Genomic_DNA. DR EMBL; BC000356; AAH00356.1; -; mRNA. DR EMBL; BC005945; AAH05945.1; -; mRNA. DR EMBL; BC070283; AAH70283.1; -; mRNA. DR CCDS; CCDS3715.1; -. [Q13257-1] DR PIR; G01942; G01942. DR RefSeq; NP_002349.1; NM_002358.3. [Q13257-1] DR PDB; 1DUJ; NMR; -; A=11-195. DR PDB; 1GO4; X-ray; 2.05 A; A/B/C/D=1-205. DR PDB; 1KLQ; NMR; -; A=11-205. DR PDB; 1S2H; NMR; -; A=1-205. DR PDB; 2QYF; X-ray; 2.30 A; A/C=1-205. DR PDB; 2V64; X-ray; 2.90 A; A/C/D/E/F/H=2-205. DR PDB; 2VFX; X-ray; 1.95 A; A/B/C/D/E/F/G/H/I/J/K/L=1-205. DR PDB; 3GMH; X-ray; 3.95 A; A/B/C/D/E/F/G/H/I/J/K/L=11-205. DR PDB; 5KHU; EM; 4.80 A; T=1-205. DR PDB; 5LCW; EM; 4.00 A; Z=1-205. DR PDB; 6F0X; EM; 4.60 A; Z=1-205. DR PDB; 6TLJ; EM; 3.80 A; Z=1-205. DR PDBsum; 1DUJ; -. DR PDBsum; 1GO4; -. DR PDBsum; 1KLQ; -. DR PDBsum; 1S2H; -. DR PDBsum; 2QYF; -. DR PDBsum; 2V64; -. DR PDBsum; 2VFX; -. DR PDBsum; 3GMH; -. DR PDBsum; 5KHU; -. DR PDBsum; 5LCW; -. DR PDBsum; 6F0X; -. DR PDBsum; 6TLJ; -. DR AlphaFoldDB; Q13257; -. DR BMRB; Q13257; -. DR EMDB; EMD-10516; -. DR EMDB; EMD-4037; -. DR EMDB; EMD-4166; -. DR SMR; Q13257; -. DR BioGRID; 110260; 250. DR ComplexPortal; CPX-3946; Mitotic Checkpoint Complex. DR ComplexPortal; CPX-85; Mitotic spindle assembly checkpoint MAD1-MAD2 complex. DR ComplexPortal; CPX-88; Mitotic spindle assembly checkpoint complex MAD2. DR CORUM; Q13257; -. DR DIP; DIP-29653N; -. DR IntAct; Q13257; 81. DR MINT; Q13257; -. DR STRING; 9606.ENSP00000296509; -. DR iPTMnet; Q13257; -. DR PhosphoSitePlus; Q13257; -. DR SwissPalm; Q13257; -. DR BioMuta; MAD2L1; -. DR DMDM; 12230256; -. DR EPD; Q13257; -. DR jPOST; Q13257; -. DR MassIVE; Q13257; -. DR MaxQB; Q13257; -. DR PaxDb; 9606-ENSP00000296509; -. DR PeptideAtlas; Q13257; -. DR ProteomicsDB; 59256; -. [Q13257-1] DR ProteomicsDB; 71439; -. DR Pumba; Q13257; -. DR TopDownProteomics; Q13257-1; -. [Q13257-1] DR ABCD; Q13257; 2 sequenced antibodies. DR Antibodypedia; 15732; 712 antibodies from 47 providers. DR DNASU; 4085; -. DR Ensembl; ENST00000296509.11; ENSP00000296509.5; ENSG00000164109.14. [Q13257-1] DR Ensembl; ENST00000333047.9; ENSP00000332295.5; ENSG00000164109.14. [Q13257-2] DR GeneID; 4085; -. DR KEGG; hsa:4085; -. DR MANE-Select; ENST00000296509.11; ENSP00000296509.5; NM_002358.4; NP_002349.1. DR UCSC; uc003idl.3; human. [Q13257-1] DR AGR; HGNC:6763; -. DR CTD; 4085; -. DR DisGeNET; 4085; -. DR GeneCards; MAD2L1; -. DR HGNC; HGNC:6763; MAD2L1. DR HPA; ENSG00000164109; Tissue enhanced (bone marrow, lymphoid tissue). DR MIM; 601467; gene. DR neXtProt; NX_Q13257; -. DR OpenTargets; ENSG00000164109; -. DR PharmGKB; PA30521; -. DR VEuPathDB; HostDB:ENSG00000164109; -. DR eggNOG; KOG3285; Eukaryota. DR GeneTree; ENSGT00940000153395; -. DR HOGENOM; CLU_072097_1_0_1; -. DR InParanoid; Q13257; -. DR OMA; ETTCAFD; -. DR OrthoDB; 5474106at2759; -. DR PhylomeDB; Q13257; -. DR TreeFam; TF101084; -. DR PathwayCommons; Q13257; -. DR Reactome; R-HSA-141405; Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components. DR Reactome; R-HSA-141430; Inactivation of APC/C via direct inhibition of the APC/C complex. DR Reactome; R-HSA-141444; Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal. DR Reactome; R-HSA-174184; Cdc20:Phospho-APC/C mediated degradation of Cyclin A. DR Reactome; R-HSA-176409; APC/C:Cdc20 mediated degradation of mitotic proteins. DR Reactome; R-HSA-179409; APC-Cdc20 mediated degradation of Nek2A. DR Reactome; R-HSA-2467813; Separation of Sister Chromatids. DR Reactome; R-HSA-2500257; Resolution of Sister Chromatid Cohesion. DR Reactome; R-HSA-5663220; RHO GTPases Activate Formins. DR Reactome; R-HSA-68877; Mitotic Prometaphase. DR Reactome; R-HSA-9648025; EML4 and NUDC in mitotic spindle formation. DR SignaLink; Q13257; -. DR SIGNOR; Q13257; -. DR BioGRID-ORCS; 4085; 774 hits in 1142 CRISPR screens. DR ChiTaRS; MAD2L1; human. DR EvolutionaryTrace; Q13257; -. DR GeneWiki; MAD2L1; -. DR GenomeRNAi; 4085; -. DR Pharos; Q13257; Tbio. DR PRO; PR:Q13257; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; Q13257; Protein. DR Bgee; ENSG00000164109; Expressed in secondary oocyte and 165 other cell types or tissues. DR ExpressionAtlas; Q13257; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0000776; C:kinetochore; IDA:UniProtKB. DR GO; GO:0033597; C:mitotic checkpoint complex; IPI:ComplexPortal. DR GO; GO:0072686; C:mitotic spindle; IDA:UniProtKB. DR GO; GO:1990728; C:mitotic spindle assembly checkpoint MAD1-MAD2 complex; IPI:ComplexPortal. DR GO; GO:0044615; C:nuclear pore nuclear basket; IDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0000922; C:spindle pole; IEA:UniProtKB-SubCell. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB. DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW. DR GO; GO:0051660; P:establishment of centrosome localization; IMP:UniProtKB. DR GO; GO:0000132; P:establishment of mitotic spindle orientation; IMP:UniProtKB. DR GO; GO:0000070; P:mitotic sister chromatid segregation; IEA:Ensembl. DR GO; GO:0007094; P:mitotic spindle assembly checkpoint signaling; IDA:UniProtKB. DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB. DR GO; GO:0045930; P:negative regulation of mitotic cell cycle; IMP:MGI. DR GO; GO:0042177; P:negative regulation of protein catabolic process; IDA:UniProtKB. DR GO; GO:1904667; P:negative regulation of ubiquitin protein ligase activity; IDA:UniProtKB. DR GO; GO:0090267; P:positive regulation of mitotic cell cycle spindle assembly checkpoint; IDA:UniProtKB. DR Gene3D; 3.30.900.10; HORMA domain; 1. DR InterPro; IPR003511; HORMA_dom. DR InterPro; IPR036570; HORMA_dom_sf. DR InterPro; IPR045091; Mad2-like. DR PANTHER; PTHR11842; MITOTIC SPINDLE ASSEMBLY CHECKPOINT PROTEIN MAD2; 1. DR PANTHER; PTHR11842:SF11; MITOTIC SPINDLE ASSEMBLY CHECKPOINT PROTEIN MAD2A; 1. DR Pfam; PF02301; HORMA; 1. DR SUPFAM; SSF56019; The spindle assembly checkpoint protein mad2; 1. DR PROSITE; PS50815; HORMA; 1. DR Genevisible; Q13257; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Cell cycle; Cell division; KW Centromere; Chromosome; Cytoplasm; Cytoskeleton; Direct protein sequencing; KW Kinetochore; Mitosis; Nucleus; Phosphoprotein; Reference proteome. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000269|Ref.12" FT CHAIN 2..205 FT /note="Mitotic spindle assembly checkpoint protein MAD2A" FT /id="PRO_0000126117" FT DOMAIN 14..197 FT /note="HORMA" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00109" FT REGION 195..205 FT /note="Required for assuming the closed conformation and FT for interaction with CDC20" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0000269|Ref.12" FT MOD_RES 6 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 130 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 170 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:12574116" FT MOD_RES 178 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:12574116" FT MOD_RES 185 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 195 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:12574116, FT ECO:0007744|PubMed:23186163" FT VAR_SEQ 74..90 FT /note="DWLYKCSVQKLVVVISN -> VHPEKSLRKLSRMKSVQ (in isoform FT 2)" FT /evidence="ECO:0000303|PubMed:14702039, ECO:0000303|Ref.6" FT /id="VSP_047644" FT VAR_SEQ 91..205 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039, ECO:0000303|Ref.6" FT /id="VSP_047645" FT MUTAGEN 13 FT /note="L->A: Leads to formation the closed conformation and FT homodimerization. Reduces binding to MAD1L1." FT /evidence="ECO:0000269|PubMed:18318601, FT ECO:0000269|PubMed:29162720" FT MUTAGEN 75 FT /note="W->A: Prevents interaction with CDC20 and leads to FT formation of the closed conformation; when associated with FT A-133." FT /evidence="ECO:0000269|PubMed:18318601" FT MUTAGEN 133 FT /note="R->A: Prevents aggregation and promotes formation of FT monomeric protein that slowly interconverts between the FT open and closed conformation." FT /evidence="ECO:0000269|PubMed:12006501" FT MUTAGEN 153 FT /note="L->A: Leads to formation of the closed conformation; FT when associated with A-133." FT /evidence="ECO:0000269|PubMed:18318601" FT MUTAGEN 156 FT /note="Y->A: Leads to formation of the closed conformation; FT when associated with A-133." FT /evidence="ECO:0000269|PubMed:18318601" FT MUTAGEN 170 FT /note="S->A: Reduces phosphorylation on serine residues; FT when associated with A-178. Abolishes phosphorylation on FT serine residues; when associated with A-178 and A-195." FT /evidence="ECO:0000269|PubMed:12574116" FT MUTAGEN 170 FT /note="S->D: Abolishes interaction with MAD1L1 and reduces FT interaction with CDC20; when associated with D-178 and FT D-195." FT /evidence="ECO:0000269|PubMed:12574116" FT MUTAGEN 178 FT /note="S->A: Reduces phosphorylation on serine residues; FT when associated with A-170. Abolishes phosphorylation on FT serine residues; when associated with A-170 and A-195." FT /evidence="ECO:0000269|PubMed:12574116" FT MUTAGEN 178 FT /note="S->D: Abolishes interaction with MAD1L1 and reduces FT interaction with CDC20; when associated with D-170 and FT D-195." FT /evidence="ECO:0000269|PubMed:12574116" FT MUTAGEN 186 FT /note="F->A: Prevents formation of the closed conformation FT and interaction with CDC20; when associated with A-133." FT /evidence="ECO:0000269|PubMed:18318601" FT MUTAGEN 188 FT /note="T->A: Prevents formation of the closed conformation FT and interaction with CDC20; when associated with A-133." FT /evidence="ECO:0000269|PubMed:18318601" FT MUTAGEN 191 FT /note="H->A: Prevents formation of the closed conformation FT and interaction with CDC20; when associated with A-133." FT /evidence="ECO:0000269|PubMed:18318601" FT MUTAGEN 195 FT /note="S->A: Abolishes phosphorylation on serine residues; FT when associated with A-170 and A-178." FT /evidence="ECO:0000269|PubMed:12574116" FT MUTAGEN 195 FT /note="S->D: Binds to the N and C-terminus of MAD1L1. FT Abolishes interaction with MAD1L1 and reduces interaction FT with CDC20; when associated with D-170 and D-178." FT /evidence="ECO:0000269|PubMed:12574116, FT ECO:0000269|PubMed:29162720" FT MUTAGEN 197 FT /note="V->A: Prevents formation of the closed conformation FT and interaction with CDC20; when associated with A-133." FT /evidence="ECO:0000269|PubMed:18318601" FT MUTAGEN 199 FT /note="Y->A: Prevents formation of the closed conformation FT and interaction with CDC20; when associated with A-133." FT /evidence="ECO:0000269|PubMed:18318601" FT CONFLICT 16 FT /note="S -> C (in Ref. 8; BAD97153)" FT /evidence="ECO:0000305" FT CONFLICT 190 FT /note="I -> V (in Ref. 11; AAH70283)" FT /evidence="ECO:0000305" FT STRAND 2..5 FT /evidence="ECO:0007829|PDB:2VFX" FT STRAND 7..9 FT /evidence="ECO:0007829|PDB:1S2H" FT HELIX 13..34 FT /evidence="ECO:0007829|PDB:2VFX" FT HELIX 40..42 FT /evidence="ECO:0007829|PDB:2VFX" FT STRAND 43..48 FT /evidence="ECO:0007829|PDB:2VFX" FT STRAND 51..56 FT /evidence="ECO:0007829|PDB:2VFX" FT HELIX 59..77 FT /evidence="ECO:0007829|PDB:2VFX" FT STRAND 78..80 FT /evidence="ECO:0007829|PDB:1DUJ" FT STRAND 81..90 FT /evidence="ECO:0007829|PDB:2VFX" FT TURN 91..93 FT /evidence="ECO:0007829|PDB:2VFX" FT STRAND 96..106 FT /evidence="ECO:0007829|PDB:2VFX" FT HELIX 108..111 FT /evidence="ECO:0007829|PDB:1GO4" FT STRAND 116..118 FT /evidence="ECO:0007829|PDB:1S2H" FT HELIX 121..139 FT /evidence="ECO:0007829|PDB:2VFX" FT STRAND 149..157 FT /evidence="ECO:0007829|PDB:2VFX" FT HELIX 160..162 FT /evidence="ECO:0007829|PDB:2QYF" FT STRAND 167..169 FT /evidence="ECO:0007829|PDB:1GO4" FT STRAND 173..175 FT /evidence="ECO:0007829|PDB:2V64" FT STRAND 177..182 FT /evidence="ECO:0007829|PDB:2VFX" FT STRAND 189..200 FT /evidence="ECO:0007829|PDB:2VFX" SQ SEQUENCE 205 AA; 23510 MW; B8DCBF0043836764 CRC64; MALQLSREQG ITLRGSAEIV AEFFSFGINS ILYQRGIYPS ETFTRVQKYG LTLLVTTDLE LIKYLNNVVE QLKDWLYKCS VQKLVVVISN IESGEVLERW QFDIECDKTA KDDSAPREKS QKAIQDEIRS VIRQITATVT FLPLLEVSCS FDLLIYTDKD LVVPEKWEES GPQFITNSEE VRLRSFTTTI HKVNSMVAYK IPVND //