Full text data of NAE1
NAE1
(APPBP1)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
NEDD8-activating enzyme E1 regulatory subunit (Amyloid beta precursor protein-binding protein 1, 59 kDa; APP-BP1; Amyloid protein-binding protein 1; Proto-oncogene protein 1)
NEDD8-activating enzyme E1 regulatory subunit (Amyloid beta precursor protein-binding protein 1, 59 kDa; APP-BP1; Amyloid protein-binding protein 1; Proto-oncogene protein 1)
hRBCD
IPI00018968
IPI00018968 Amyloid protein-binding protein 1 The dimeric enzyme activates NEDD8 by first adenylating its C-terminal glycine residue with ATP and thereafter linking this residue to the side chain of a cysteine residue on UBE1C soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
IPI00018968 Amyloid protein-binding protein 1 The dimeric enzyme activates NEDD8 by first adenylating its C-terminal glycine residue with ATP and thereafter linking this residue to the side chain of a cysteine residue on UBE1C soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
UniProt
Q13564
ID ULA1_HUMAN Reviewed; 534 AA.
AC Q13564; A6NFN4; B2R700;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1996, sequence version 1.
DT 22-JAN-2014, entry version 127.
DE RecName: Full=NEDD8-activating enzyme E1 regulatory subunit;
DE AltName: Full=Amyloid beta precursor protein-binding protein 1, 59 kDa;
DE Short=APP-BP1;
DE AltName: Full=Amyloid protein-binding protein 1;
DE AltName: Full=Proto-oncogene protein 1;
GN Name=NAE1; Synonyms=APPBP1; ORFNames=HPP1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH APP, AND
RP TISSUE SPECIFICITY.
RC TISSUE=Fetal brain, and Fetal skeletal muscle;
RX PubMed=8626687; DOI=10.1074/jbc.271.19.11339;
RA Chow N., Korenberg J.R., Chen X.-N., Neve R.L.;
RT "APP-BP1, a novel protein that binds to the carboxyl-terminal region
RT of the amyloid precursor protein.";
RL J. Biol. Chem. 271:11339-11346(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kim J.W.;
RT "Identification of a new human protooncogene.";
RL Submitted (DEC-2002) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Testis;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10493829; DOI=10.1006/geno.1999.5927;
RA Loftus B.J., Kim U.-J., Sneddon V.P., Kalush F., Brandon R.,
RA Fuhrmann J., Mason T., Crosby M.L., Barnstead M., Cronin L.,
RA Mays A.D., Cao Y., Xu R.X., Kang H.-L., Mitchell S., Eichler E.E.,
RA Harris P.C., Venter J.C., Adams M.D.;
RT "Genome duplications and other features in 12 Mb of DNA sequence from
RT human chromosome 16p and 16q.";
RL Genomics 60:295-308(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Testis;
RX PubMed=11230166; DOI=10.1101/gr.GR1547R;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H.,
RA Lauber J., Duesterhoeft A., Beyer A., Koehrer K., Strack N.,
RA Mewes H.-W., Ottenwaelder B., Obermaier B., Tampe J., Heubner D.,
RA Wambutt R., Korn B., Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and
RT analysis of 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X.,
RA Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A.,
RA Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J.,
RA Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L.,
RA Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A.,
RA Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D.,
RA Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J.,
RA Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I.,
RA Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W.,
RA Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A.,
RA Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S.,
RA Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L.,
RA Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A.,
RA Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L.,
RA Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N.,
RA Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M.,
RA Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L.,
RA Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D.,
RA Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P.,
RA Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M.,
RA Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP FUNCTION.
RX PubMed=10207026; DOI=10.1074/jbc.274.17.12036;
RA Gong L., Yeh E.T.H.;
RT "Identification of the activating and conjugating enzymes of the NEDD8
RT conjugation pathway.";
RL J. Biol. Chem. 274:12036-12042(1999).
RN [10]
RP FUNCTION, AND INTERACTION WITH UBA3.
RX PubMed=10722740; DOI=10.1074/jbc.275.12.8929;
RA Chen Y., McPhie D.L., Hirschberg J., Neve R.L.;
RT "The amyloid precursor protein-binding protein APP-BP1 drives the cell
RT cycle through the S-M checkpoint and causes apoptosis in neurons.";
RL J. Biol. Chem. 275:8929-8935(2000).
RN [11]
RP FUNCTION, AND INTERACTION WITH UBA3.
RX PubMed=12740388; DOI=10.1074/jbc.M303177200;
RA Bohnsack R.N., Haas A.L.;
RT "Conservation in the mechanism of Nedd8 activation by the human
RT AppBp1-Uba3 heterodimer.";
RL J. Biol. Chem. 278:26823-26830(2003).
RN [12]
RP INTERACTION WITH APP, AND SUBCELLULAR LOCATION.
RX PubMed=14557245; DOI=10.1083/jcb.200304003;
RA Chen Y., Liu W., McPhie D.L., Hassinger L., Neve R.L.;
RT "APP-BP1 mediates APP-induced apoptosis and DNA synthesis and is
RT increased in Alzheimer's disease brain.";
RL J. Cell Biol. 163:27-33(2003).
RN [13]
RP INTERACTION WITH TP53BP2.
RX PubMed=12694406;
RA Chen Y., Liu W., Naumovski L., Neve R.L.;
RT "ASPP2 inhibits APP-BP1-mediated NEDD8 conjugation to cullin-1 and
RT decreases APP-BP1-induced cell proliferation and neuronal apoptosis.";
RL J. Neurochem. 85:801-809(2003).
RN [14]
RP UBIQUITINATION.
RX PubMed=18627766; DOI=10.1016/j.bbrc.2008.07.019;
RA Park Y., Yoon S.K., Yoon J.B.;
RT "TRIP12 functions as an E3 ubiquitin ligase of APP-BP1.";
RL Biochem. Biophys. Res. Commun. 374:294-298(2008).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2 AND LYS-6, MASS
RP SPECTROMETRY, AND CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [16]
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.,
RA Buerckstuemmer T., 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 [17]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 5-534 IN COMPLEX WITH UBA3;
RP NEDD8 AND ATP.
RX PubMed=14690597; DOI=10.1016/S1097-2765(03)00452-0;
RA Walden H., Podgorski M.S., Huang D.T., Miller D.W., Howard R.J.,
RA Minor D.L. Jr., Holton J.M., Schulman B.A.;
RT "The structure of the APPBP1-UBA3-NEDD8-ATP complex reveals the basis
RT for selective ubiquitin-like protein activation by an E1.";
RL Mol. Cell 12:1427-1437(2003).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 5-534 IN COMPLEX WITH UBA3,
RP AND MUTAGENESIS OF ASP-331.
RX PubMed=12646924; DOI=10.1038/nature01456;
RA Walden H., Podgorski M.S., Schulman B.A.;
RT "Insights into the ubiquitin transfer cascade from the structure of
RT the activating enzyme for NEDD8.";
RL Nature 422:330-334(2003).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) IN COMPLEX WITH UBA3 AND UBE2M.
RX PubMed=15361859; DOI=10.1038/nsmb826;
RA Huang D.T., Miller D.W., Mathew R., Cassell R., Holton J.M.,
RA Roussel M.F., Schulman B.A.;
RT "A unique E1-E2 interaction required for optimal conjugation of the
RT ubiquitin-like protein NEDD8.";
RL Nat. Struct. Mol. Biol. 11:927-935(2004).
CC -!- FUNCTION: Regulatory subunit of the dimeric UBA3-NAE1 E1 enzyme.
CC E1 activates NEDD8 by first adenylating its C-terminal glycine
CC residue with ATP, thereafter linking this residue to the side
CC chain of the catalytic cysteine, yielding a NEDD8-UBA3 thioester
CC and free AMP. E1 finally transfers NEDD8 to the catalytic cysteine
CC of UBE2M. Necessary for cell cycle progression through the S-M
CC checkpoint. Overexpression of NAE1 causes apoptosis through
CC deregulation of NEDD8 conjugation.
CC -!- ENZYME REGULATION: Binding of TP53BP2 to the regulatory subunit
CC NAE1 decreases neddylation activity.
CC -!- PATHWAY: Protein modification; protein neddylation.
CC -!- SUBUNIT: Heterodimer of UBA3 and NAE1. The complex binds NEDD8 and
CC UBE2M. Binds APP and TP53BP2.
CC -!- SUBCELLULAR LOCATION: Cell membrane. Note=Colocalizes with APP in
CC lipid rafts.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q13564-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q13564-2; Sequence=VSP_042895;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Ubiquitous in fetal tissues. Expressed
CC throughout the adult brain.
CC -!- PTM: Ubiquitinated by TRIP12, leading to its degradation by the
CC proteasome.
CC -!- MISCELLANEOUS: NAE1 and UBA3 correspond to the N-terminal and the
CC C-terminal part of yeast UBA3. In yeast the two subunits form a
CC single polypeptide chain.
CC -!- SIMILARITY: Belongs to the ubiquitin-activating E1 family. ULA1
CC subfamily.
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DR EMBL; U50939; AAC50477.1; -; mRNA.
DR EMBL; AY197612; AAP35030.1; -; mRNA.
DR EMBL; AK298159; BAH12735.1; -; mRNA.
DR EMBL; AK312784; BAG35647.1; -; mRNA.
DR EMBL; AC004638; AAC23784.1; -; Genomic_DNA.
DR EMBL; AC044802; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL136798; CAB66732.1; -; mRNA.
DR EMBL; CH471092; EAW83042.1; -; Genomic_DNA.
DR EMBL; BC000480; AAH00480.1; -; mRNA.
DR EMBL; BC013301; AAH13301.1; -; mRNA.
DR RefSeq; NP_001018169.1; NM_001018159.1.
DR RefSeq; NP_001018170.1; NM_001018160.1.
DR RefSeq; NP_001273429.1; NM_001286500.1.
DR RefSeq; NP_003896.1; NM_003905.3.
DR UniGene; Hs.460978; -.
DR PDB; 1R4M; X-ray; 3.00 A; A/C/E/G=1-534.
DR PDB; 1R4N; X-ray; 3.60 A; A/C/E/G=1-534.
DR PDB; 1TT5; X-ray; 2.60 A; A/C=1-534.
DR PDB; 1YOV; X-ray; 2.60 A; A/C=1-534.
DR PDB; 2NVU; X-ray; 2.80 A; A=1-534.
DR PDB; 3DBH; X-ray; 2.85 A; A/C/E/G=1-534.
DR PDB; 3DBL; X-ray; 2.90 A; A/C/E/G=1-534.
DR PDB; 3DBR; X-ray; 3.05 A; A/C/E/G=1-534.
DR PDB; 3GZN; X-ray; 3.00 A; A/C=1-534.
DR PDBsum; 1R4M; -.
DR PDBsum; 1R4N; -.
DR PDBsum; 1TT5; -.
DR PDBsum; 1YOV; -.
DR PDBsum; 2NVU; -.
DR PDBsum; 3DBH; -.
DR PDBsum; 3DBL; -.
DR PDBsum; 3DBR; -.
DR PDBsum; 3GZN; -.
DR ProteinModelPortal; Q13564; -.
DR SMR; Q13564; 6-534.
DR IntAct; Q13564; 6.
DR MINT; MINT-1429663; -.
DR STRING; 9606.ENSP00000290810; -.
DR ChEMBL; CHEMBL2016431; -.
DR DrugBank; DB00171; Adenosine triphosphate.
DR PhosphoSite; Q13564; -.
DR DMDM; 50400302; -.
DR PaxDb; Q13564; -.
DR PRIDE; Q13564; -.
DR DNASU; 8883; -.
DR Ensembl; ENST00000290810; ENSP00000290810; ENSG00000159593.
DR Ensembl; ENST00000379463; ENSP00000368776; ENSG00000159593.
DR GeneID; 8883; -.
DR KEGG; hsa:8883; -.
DR UCSC; uc002eqf.3; human.
DR CTD; 8883; -.
DR GeneCards; GC16M066836; -.
DR HGNC; HGNC:621; NAE1.
DR HPA; HPA041178; -.
DR HPA; HPA042041; -.
DR MIM; 603385; gene.
DR neXtProt; NX_Q13564; -.
DR PharmGKB; PA162396730; -.
DR eggNOG; COG0476; -.
DR HOGENOM; HOG000216537; -.
DR HOVERGEN; HBG079761; -.
DR KO; K04532; -.
DR PhylomeDB; Q13564; -.
DR UniPathway; UPA00885; -.
DR ChiTaRS; NAE1; human.
DR EvolutionaryTrace; Q13564; -.
DR GeneWiki; APPBP1; -.
DR GenomeRNAi; 8883; -.
DR NextBio; 33357; -.
DR PRO; PR:Q13564; -.
DR ArrayExpress; Q13564; -.
DR Bgee; Q13564; -.
DR CleanEx; HS_NAE1; -.
DR Genevestigator; Q13564; -.
DR GO; GO:0005737; C:cytoplasm; TAS:ProtInc.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0003824; F:catalytic activity; IEA:InterPro.
DR GO; GO:0033314; P:mitotic DNA replication checkpoint; IDA:UniProtKB.
DR GO; GO:0051402; P:neuron apoptotic process; IDA:UniProtKB.
DR GO; GO:0045116; P:protein neddylation; IDA:UniProtKB.
DR GO; GO:0043523; P:regulation of neuron apoptotic process; IDA:UniProtKB.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR Gene3D; 3.40.50.720; -; 3.
DR InterPro; IPR009036; Molybdenum_cofac_synth_MoeB.
DR InterPro; IPR016040; NAD(P)-bd_dom.
DR InterPro; IPR000594; ThiF_NAD_FAD-bd.
DR Pfam; PF00899; ThiF; 1.
DR SUPFAM; SSF69572; SSF69572; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Apoptosis;
KW Cell cycle; Cell membrane; Complete proteome; Membrane; Polymorphism;
KW Reference proteome; Ubl conjugation; Ubl conjugation pathway.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 534 NEDD8-activating enzyme E1 regulatory
FT subunit.
FT /FTId=PRO_0000194951.
FT REGION 331 344 Interaction with UBA3.
FT SITE 211 211 Interaction with UBA3.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 6 6 N6-acetyllysine.
FT VAR_SEQ 1 17 MAQLGKLLKEQKYDRQL -> MDAQQTKTNEA (in
FT isoform 2).
FT /FTId=VSP_042895.
FT VARIANT 101 101 S -> F (in dbSNP:rs363212).
FT /FTId=VAR_052435.
FT MUTAGEN 331 331 D->A: Impairs the formation of the NEDD8-
FT UBA3 thioester.
FT HELIX 3 12
FT HELIX 14 30
FT STRAND 32 36
FT HELIX 40 50
FT TURN 51 53
FT STRAND 55 60
FT HELIX 67 72
FT HELIX 78 80
FT HELIX 85 94
FT STRAND 104 107
FT HELIX 109 114
FT HELIX 117 122
FT STRAND 124 130
FT HELIX 133 145
FT STRAND 150 156
FT STRAND 159 165
FT STRAND 169 172
FT STRAND 185 187
FT HELIX 190 197
FT STRAND 201 204
FT HELIX 209 211
FT HELIX 214 225
FT TURN 226 229
FT HELIX 236 249
FT STRAND 257 259
FT HELIX 262 275
FT HELIX 283 289
FT HELIX 292 295
FT STRAND 299 301
FT HELIX 303 316
FT TURN 317 321
FT HELIX 336 366
FT TURN 367 369
FT STRAND 372 375
FT HELIX 377 385
FT HELIX 387 389
FT STRAND 391 393
FT HELIX 398 402
FT TURN 404 406
FT HELIX 409 415
FT HELIX 423 439
FT TURN 447 449
FT HELIX 450 467
FT HELIX 476 484
FT TURN 485 487
FT HELIX 491 510
FT STRAND 520 523
FT TURN 524 527
FT STRAND 528 531
SQ SEQUENCE 534 AA; 60246 MW; 5EC8D3ACE6374F21 CRC64;
MAQLGKLLKE QKYDRQLRLW GDHGQEALES AHVCLINATA TGTEILKNLV LPGIGSFTII
DGNQVSGEDA GNNFFLQRSS IGKNRAEAAM EFLQELNSDV SGSFVEESPE NLLDNDPSFF
CRFTVVVATQ LPESTSLRLA DVLWNSQIPL LICRTYGLVG YMRIIIKEHP VIESHPDNAL
EDLRLDKPFP ELREHFQSYD LDHMEKKDHS HTPWIVIIAK YLAQWYSETN GRIPKTYKEK
EDFRDLIRQG ILKNENGAPE DEENFEEAIK NVNTALNTTQ IPSSIEDIFN DDRCINITKQ
TPSFWILARA LKEFVAKEGQ GNLPVRGTIP DMIADSGKYI KLQNVYREKA KKDAAAVGNH
VAKLLQSIGQ APESISEKEL KLLCSNSAFL RVVRCRSLAE EYGLDTINKD EIISSMDNPD
NEIVLYLMLR AVDRFHKQQG RYPGVSNYQV EEDIGKLKSC LTGFLQEYGL SVMVKDDYVH
EFCRYGAAEP HTIAAFLGGA AAQEVIKIIT KQFVIFNNTY IYSGMSQTSA TFQL
//
ID ULA1_HUMAN Reviewed; 534 AA.
AC Q13564; A6NFN4; B2R700;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1996, sequence version 1.
DT 22-JAN-2014, entry version 127.
DE RecName: Full=NEDD8-activating enzyme E1 regulatory subunit;
DE AltName: Full=Amyloid beta precursor protein-binding protein 1, 59 kDa;
DE Short=APP-BP1;
DE AltName: Full=Amyloid protein-binding protein 1;
DE AltName: Full=Proto-oncogene protein 1;
GN Name=NAE1; Synonyms=APPBP1; ORFNames=HPP1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH APP, AND
RP TISSUE SPECIFICITY.
RC TISSUE=Fetal brain, and Fetal skeletal muscle;
RX PubMed=8626687; DOI=10.1074/jbc.271.19.11339;
RA Chow N., Korenberg J.R., Chen X.-N., Neve R.L.;
RT "APP-BP1, a novel protein that binds to the carboxyl-terminal region
RT of the amyloid precursor protein.";
RL J. Biol. Chem. 271:11339-11346(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kim J.W.;
RT "Identification of a new human protooncogene.";
RL Submitted (DEC-2002) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Testis;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10493829; DOI=10.1006/geno.1999.5927;
RA Loftus B.J., Kim U.-J., Sneddon V.P., Kalush F., Brandon R.,
RA Fuhrmann J., Mason T., Crosby M.L., Barnstead M., Cronin L.,
RA Mays A.D., Cao Y., Xu R.X., Kang H.-L., Mitchell S., Eichler E.E.,
RA Harris P.C., Venter J.C., Adams M.D.;
RT "Genome duplications and other features in 12 Mb of DNA sequence from
RT human chromosome 16p and 16q.";
RL Genomics 60:295-308(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Testis;
RX PubMed=11230166; DOI=10.1101/gr.GR1547R;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H.,
RA Lauber J., Duesterhoeft A., Beyer A., Koehrer K., Strack N.,
RA Mewes H.-W., Ottenwaelder B., Obermaier B., Tampe J., Heubner D.,
RA Wambutt R., Korn B., Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and
RT analysis of 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X.,
RA Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A.,
RA Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J.,
RA Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L.,
RA Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A.,
RA Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D.,
RA Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J.,
RA Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I.,
RA Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W.,
RA Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A.,
RA Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S.,
RA Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L.,
RA Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A.,
RA Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L.,
RA Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N.,
RA Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M.,
RA Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L.,
RA Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D.,
RA Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P.,
RA Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M.,
RA Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP FUNCTION.
RX PubMed=10207026; DOI=10.1074/jbc.274.17.12036;
RA Gong L., Yeh E.T.H.;
RT "Identification of the activating and conjugating enzymes of the NEDD8
RT conjugation pathway.";
RL J. Biol. Chem. 274:12036-12042(1999).
RN [10]
RP FUNCTION, AND INTERACTION WITH UBA3.
RX PubMed=10722740; DOI=10.1074/jbc.275.12.8929;
RA Chen Y., McPhie D.L., Hirschberg J., Neve R.L.;
RT "The amyloid precursor protein-binding protein APP-BP1 drives the cell
RT cycle through the S-M checkpoint and causes apoptosis in neurons.";
RL J. Biol. Chem. 275:8929-8935(2000).
RN [11]
RP FUNCTION, AND INTERACTION WITH UBA3.
RX PubMed=12740388; DOI=10.1074/jbc.M303177200;
RA Bohnsack R.N., Haas A.L.;
RT "Conservation in the mechanism of Nedd8 activation by the human
RT AppBp1-Uba3 heterodimer.";
RL J. Biol. Chem. 278:26823-26830(2003).
RN [12]
RP INTERACTION WITH APP, AND SUBCELLULAR LOCATION.
RX PubMed=14557245; DOI=10.1083/jcb.200304003;
RA Chen Y., Liu W., McPhie D.L., Hassinger L., Neve R.L.;
RT "APP-BP1 mediates APP-induced apoptosis and DNA synthesis and is
RT increased in Alzheimer's disease brain.";
RL J. Cell Biol. 163:27-33(2003).
RN [13]
RP INTERACTION WITH TP53BP2.
RX PubMed=12694406;
RA Chen Y., Liu W., Naumovski L., Neve R.L.;
RT "ASPP2 inhibits APP-BP1-mediated NEDD8 conjugation to cullin-1 and
RT decreases APP-BP1-induced cell proliferation and neuronal apoptosis.";
RL J. Neurochem. 85:801-809(2003).
RN [14]
RP UBIQUITINATION.
RX PubMed=18627766; DOI=10.1016/j.bbrc.2008.07.019;
RA Park Y., Yoon S.K., Yoon J.B.;
RT "TRIP12 functions as an E3 ubiquitin ligase of APP-BP1.";
RL Biochem. Biophys. Res. Commun. 374:294-298(2008).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2 AND LYS-6, MASS
RP SPECTROMETRY, AND CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [16]
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.,
RA Buerckstuemmer T., 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 [17]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 5-534 IN COMPLEX WITH UBA3;
RP NEDD8 AND ATP.
RX PubMed=14690597; DOI=10.1016/S1097-2765(03)00452-0;
RA Walden H., Podgorski M.S., Huang D.T., Miller D.W., Howard R.J.,
RA Minor D.L. Jr., Holton J.M., Schulman B.A.;
RT "The structure of the APPBP1-UBA3-NEDD8-ATP complex reveals the basis
RT for selective ubiquitin-like protein activation by an E1.";
RL Mol. Cell 12:1427-1437(2003).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 5-534 IN COMPLEX WITH UBA3,
RP AND MUTAGENESIS OF ASP-331.
RX PubMed=12646924; DOI=10.1038/nature01456;
RA Walden H., Podgorski M.S., Schulman B.A.;
RT "Insights into the ubiquitin transfer cascade from the structure of
RT the activating enzyme for NEDD8.";
RL Nature 422:330-334(2003).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) IN COMPLEX WITH UBA3 AND UBE2M.
RX PubMed=15361859; DOI=10.1038/nsmb826;
RA Huang D.T., Miller D.W., Mathew R., Cassell R., Holton J.M.,
RA Roussel M.F., Schulman B.A.;
RT "A unique E1-E2 interaction required for optimal conjugation of the
RT ubiquitin-like protein NEDD8.";
RL Nat. Struct. Mol. Biol. 11:927-935(2004).
CC -!- FUNCTION: Regulatory subunit of the dimeric UBA3-NAE1 E1 enzyme.
CC E1 activates NEDD8 by first adenylating its C-terminal glycine
CC residue with ATP, thereafter linking this residue to the side
CC chain of the catalytic cysteine, yielding a NEDD8-UBA3 thioester
CC and free AMP. E1 finally transfers NEDD8 to the catalytic cysteine
CC of UBE2M. Necessary for cell cycle progression through the S-M
CC checkpoint. Overexpression of NAE1 causes apoptosis through
CC deregulation of NEDD8 conjugation.
CC -!- ENZYME REGULATION: Binding of TP53BP2 to the regulatory subunit
CC NAE1 decreases neddylation activity.
CC -!- PATHWAY: Protein modification; protein neddylation.
CC -!- SUBUNIT: Heterodimer of UBA3 and NAE1. The complex binds NEDD8 and
CC UBE2M. Binds APP and TP53BP2.
CC -!- SUBCELLULAR LOCATION: Cell membrane. Note=Colocalizes with APP in
CC lipid rafts.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q13564-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q13564-2; Sequence=VSP_042895;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Ubiquitous in fetal tissues. Expressed
CC throughout the adult brain.
CC -!- PTM: Ubiquitinated by TRIP12, leading to its degradation by the
CC proteasome.
CC -!- MISCELLANEOUS: NAE1 and UBA3 correspond to the N-terminal and the
CC C-terminal part of yeast UBA3. In yeast the two subunits form a
CC single polypeptide chain.
CC -!- SIMILARITY: Belongs to the ubiquitin-activating E1 family. ULA1
CC subfamily.
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DR EMBL; U50939; AAC50477.1; -; mRNA.
DR EMBL; AY197612; AAP35030.1; -; mRNA.
DR EMBL; AK298159; BAH12735.1; -; mRNA.
DR EMBL; AK312784; BAG35647.1; -; mRNA.
DR EMBL; AC004638; AAC23784.1; -; Genomic_DNA.
DR EMBL; AC044802; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL136798; CAB66732.1; -; mRNA.
DR EMBL; CH471092; EAW83042.1; -; Genomic_DNA.
DR EMBL; BC000480; AAH00480.1; -; mRNA.
DR EMBL; BC013301; AAH13301.1; -; mRNA.
DR RefSeq; NP_001018169.1; NM_001018159.1.
DR RefSeq; NP_001018170.1; NM_001018160.1.
DR RefSeq; NP_001273429.1; NM_001286500.1.
DR RefSeq; NP_003896.1; NM_003905.3.
DR UniGene; Hs.460978; -.
DR PDB; 1R4M; X-ray; 3.00 A; A/C/E/G=1-534.
DR PDB; 1R4N; X-ray; 3.60 A; A/C/E/G=1-534.
DR PDB; 1TT5; X-ray; 2.60 A; A/C=1-534.
DR PDB; 1YOV; X-ray; 2.60 A; A/C=1-534.
DR PDB; 2NVU; X-ray; 2.80 A; A=1-534.
DR PDB; 3DBH; X-ray; 2.85 A; A/C/E/G=1-534.
DR PDB; 3DBL; X-ray; 2.90 A; A/C/E/G=1-534.
DR PDB; 3DBR; X-ray; 3.05 A; A/C/E/G=1-534.
DR PDB; 3GZN; X-ray; 3.00 A; A/C=1-534.
DR PDBsum; 1R4M; -.
DR PDBsum; 1R4N; -.
DR PDBsum; 1TT5; -.
DR PDBsum; 1YOV; -.
DR PDBsum; 2NVU; -.
DR PDBsum; 3DBH; -.
DR PDBsum; 3DBL; -.
DR PDBsum; 3DBR; -.
DR PDBsum; 3GZN; -.
DR ProteinModelPortal; Q13564; -.
DR SMR; Q13564; 6-534.
DR IntAct; Q13564; 6.
DR MINT; MINT-1429663; -.
DR STRING; 9606.ENSP00000290810; -.
DR ChEMBL; CHEMBL2016431; -.
DR DrugBank; DB00171; Adenosine triphosphate.
DR PhosphoSite; Q13564; -.
DR DMDM; 50400302; -.
DR PaxDb; Q13564; -.
DR PRIDE; Q13564; -.
DR DNASU; 8883; -.
DR Ensembl; ENST00000290810; ENSP00000290810; ENSG00000159593.
DR Ensembl; ENST00000379463; ENSP00000368776; ENSG00000159593.
DR GeneID; 8883; -.
DR KEGG; hsa:8883; -.
DR UCSC; uc002eqf.3; human.
DR CTD; 8883; -.
DR GeneCards; GC16M066836; -.
DR HGNC; HGNC:621; NAE1.
DR HPA; HPA041178; -.
DR HPA; HPA042041; -.
DR MIM; 603385; gene.
DR neXtProt; NX_Q13564; -.
DR PharmGKB; PA162396730; -.
DR eggNOG; COG0476; -.
DR HOGENOM; HOG000216537; -.
DR HOVERGEN; HBG079761; -.
DR KO; K04532; -.
DR PhylomeDB; Q13564; -.
DR UniPathway; UPA00885; -.
DR ChiTaRS; NAE1; human.
DR EvolutionaryTrace; Q13564; -.
DR GeneWiki; APPBP1; -.
DR GenomeRNAi; 8883; -.
DR NextBio; 33357; -.
DR PRO; PR:Q13564; -.
DR ArrayExpress; Q13564; -.
DR Bgee; Q13564; -.
DR CleanEx; HS_NAE1; -.
DR Genevestigator; Q13564; -.
DR GO; GO:0005737; C:cytoplasm; TAS:ProtInc.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0003824; F:catalytic activity; IEA:InterPro.
DR GO; GO:0033314; P:mitotic DNA replication checkpoint; IDA:UniProtKB.
DR GO; GO:0051402; P:neuron apoptotic process; IDA:UniProtKB.
DR GO; GO:0045116; P:protein neddylation; IDA:UniProtKB.
DR GO; GO:0043523; P:regulation of neuron apoptotic process; IDA:UniProtKB.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR Gene3D; 3.40.50.720; -; 3.
DR InterPro; IPR009036; Molybdenum_cofac_synth_MoeB.
DR InterPro; IPR016040; NAD(P)-bd_dom.
DR InterPro; IPR000594; ThiF_NAD_FAD-bd.
DR Pfam; PF00899; ThiF; 1.
DR SUPFAM; SSF69572; SSF69572; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Apoptosis;
KW Cell cycle; Cell membrane; Complete proteome; Membrane; Polymorphism;
KW Reference proteome; Ubl conjugation; Ubl conjugation pathway.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 534 NEDD8-activating enzyme E1 regulatory
FT subunit.
FT /FTId=PRO_0000194951.
FT REGION 331 344 Interaction with UBA3.
FT SITE 211 211 Interaction with UBA3.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 6 6 N6-acetyllysine.
FT VAR_SEQ 1 17 MAQLGKLLKEQKYDRQL -> MDAQQTKTNEA (in
FT isoform 2).
FT /FTId=VSP_042895.
FT VARIANT 101 101 S -> F (in dbSNP:rs363212).
FT /FTId=VAR_052435.
FT MUTAGEN 331 331 D->A: Impairs the formation of the NEDD8-
FT UBA3 thioester.
FT HELIX 3 12
FT HELIX 14 30
FT STRAND 32 36
FT HELIX 40 50
FT TURN 51 53
FT STRAND 55 60
FT HELIX 67 72
FT HELIX 78 80
FT HELIX 85 94
FT STRAND 104 107
FT HELIX 109 114
FT HELIX 117 122
FT STRAND 124 130
FT HELIX 133 145
FT STRAND 150 156
FT STRAND 159 165
FT STRAND 169 172
FT STRAND 185 187
FT HELIX 190 197
FT STRAND 201 204
FT HELIX 209 211
FT HELIX 214 225
FT TURN 226 229
FT HELIX 236 249
FT STRAND 257 259
FT HELIX 262 275
FT HELIX 283 289
FT HELIX 292 295
FT STRAND 299 301
FT HELIX 303 316
FT TURN 317 321
FT HELIX 336 366
FT TURN 367 369
FT STRAND 372 375
FT HELIX 377 385
FT HELIX 387 389
FT STRAND 391 393
FT HELIX 398 402
FT TURN 404 406
FT HELIX 409 415
FT HELIX 423 439
FT TURN 447 449
FT HELIX 450 467
FT HELIX 476 484
FT TURN 485 487
FT HELIX 491 510
FT STRAND 520 523
FT TURN 524 527
FT STRAND 528 531
SQ SEQUENCE 534 AA; 60246 MW; 5EC8D3ACE6374F21 CRC64;
MAQLGKLLKE QKYDRQLRLW GDHGQEALES AHVCLINATA TGTEILKNLV LPGIGSFTII
DGNQVSGEDA GNNFFLQRSS IGKNRAEAAM EFLQELNSDV SGSFVEESPE NLLDNDPSFF
CRFTVVVATQ LPESTSLRLA DVLWNSQIPL LICRTYGLVG YMRIIIKEHP VIESHPDNAL
EDLRLDKPFP ELREHFQSYD LDHMEKKDHS HTPWIVIIAK YLAQWYSETN GRIPKTYKEK
EDFRDLIRQG ILKNENGAPE DEENFEEAIK NVNTALNTTQ IPSSIEDIFN DDRCINITKQ
TPSFWILARA LKEFVAKEGQ GNLPVRGTIP DMIADSGKYI KLQNVYREKA KKDAAAVGNH
VAKLLQSIGQ APESISEKEL KLLCSNSAFL RVVRCRSLAE EYGLDTINKD EIISSMDNPD
NEIVLYLMLR AVDRFHKQQG RYPGVSNYQV EEDIGKLKSC LTGFLQEYGL SVMVKDDYVH
EFCRYGAAEP HTIAAFLGGA AAQEVIKIIT KQFVIFNNTY IYSGMSQTSA TFQL
//
MIM
603385
*RECORD*
*FIELD* NO
603385
*FIELD* TI
*603385 NEDD8-ACTIVATING ENZYME E1, SUBUNIT 1; NAE1
;;AMYLOID BETA PRECURSOR PROTEIN-BINDING PROTEIN 1; APPBP1
read more*FIELD* TX
CLONING
Beta-amyloid precursor protein (APP; 104760) is a cell surface protein
that has structural features characteristic of cell surface receptors
with signal-transducing properties. To identify proteins with the
potential to bind and interact with APP, Chow et al. (1996) used a
C-terminal fragment of APP to screen a human fetal brain cDNA expression
library. They isolated cDNAs encoding an APP-binding protein, which they
designated APPBP1. Chow et al. (1996) demonstrated that the deduced
534-amino acid, 59-kD APPBP1 protein interacts with the C-terminal
region of APP in in vitro binding assays and with full-length APP from
mammalian cells in immunoprecipitation assays. The APPBP1 protein is 39%
identical to the protein encoded by the Arabidopsis auxin resistance
gene AXR1; both proteins are relatives of ubiquitin-activating enzyme-1
(UBE1; 314370). Northern blot analysis of human tissues revealed that
the single-copy APPBP1 gene is ubiquitously expressed as a 1.8-kb
transcript. In situ hybridization histochemistry showed that Appbp1 mRNA
is expressed throughout the rat brain.
MAPPING
Chow et al. (1996) localized the APPBP1 gene to 16q22 by fluorescence in
situ hybridization.
GENE FUNCTION
Ubiquitin (191339) is covalently attached to target proteins by a
multienzymatic system consisting of E1 (ubiquitin-activating), E2
(ubiquitin-conjugating), and E3 (ubiquitin-ligating) enzymes. Osaka et
al. (1998) found that NEDD8 (603171), a ubiquitin-like protein, is
conjugated to proteins in a manner analogous to ubiquitylation. They
found that APPBP1 can bind to NEDD8 in rabbit reticulocyte lysates.
However, since APPBP1 shows similarity to only the N-terminal domain of
an E1 enzyme, the authors reasoned that it must interact with a protein
showing similarity to the C-terminal region of E1s. By searching
sequence databases, Osaka et al. (1998) identified cDNAs encoding UBA3
(603172), the human homolog of yeast Uba3. In vitro, UBA3 formed a
complex with APPBP1 and a thioester linkage with NEDD8. Osaka et al.
(1998) suggested that the APPBP1/UBA3 complex functions as an E1-like
enzyme for the activation of NEDD8.
Ts41 mutant Chinese hamster cells show a temperature-sensitive defect in
the cell cycle and undergo successive S phases without intervening G2,
M, and G1 phases. The phenotype suggests that the mutated gene
negatively regulates entry into S phase and positively regulates entry
into mitosis. Chen et al. (2000) showed that human APPBP1 corrected the
ts41 defect. Overexpression of human APPBP1 in rat primary cortical
neurons caused apoptosis, and this effect required the UBA3-binding
domain of APPBP1. Dominant-negative human UBA3 and UBC12 (UBE2M; 603173)
mutants inhibited the ability of APPBP1 to cause apoptosis, implicating
the NEDD8 conjugation pathway. In addition, a specific caspase-6 (CASP6;
601532) inhibitor blocked APPBP1-induced apoptosis.
Walden et al. (2003) reported the structure and mutational analysis of
human APPBP1-UBA3, the heterodimeric E1 enzyme for NEDD8. Each E1
activity is specified by a domain: an adenylation domain resembling
bacterial adenylating enzymes, an E1-specific domain organized around
the catalytic cysteine, and a domain involved in E2 recognition
resembling ubiquitin. The domains are arranged around 2 clefts that
coordinate protein and nucleotide binding so that each of E1's reactions
drives the next, in an assembly-line fashion.
NEDD8 is first activated by an E1 enzyme, NEDD8-activating enzyme (NAE,
a heterodimer of NAE1 and UBA3 subunits), transferred to an E2 enzyme
(UBE2M), and then conjugated to target substrates. The NAE controls the
activity of the cullin-RING subtype of ubiquitin ligases, thereby
regulating the turnover of a subset of proteins upstream of the
proteasome. Substrates of cullin-RING ligases have important roles in
cellular processes associated with cancer cell growth and survival
pathways. Soucy et al. (2009) described MLN4924, a potent and selective
inhibitor of NAE. MLN4924 disrupts cullin-RING ligase-mediated protein
turnover leading to apoptotic death in human tumor cells by a novel
mechanism of action, the deregulation of S-phase DNA synthesis. MLN4924
suppressed the growth of human tumor xenografts in mice at compound
exposures that were well tolerated. Soucy et al. (2009) concluded that
NAE inhibitors may hold promise for the treatment of cancer.
BIOCHEMICAL FEATURES
Bohnsack and Haas (2003) purified APPBP1-UBA3 from human erythrocytes
and analyzed the kinetics of NEDD8 activation. In the presence of
radiolabeled ATP and radiolabeled recombinant NEDD8, APPBP1-UBA3 rapidly
formed a stable stoichiometric ternary complex composed of tightly bound
NEDD8 adenylate and UBA3-NEDD8 thiol ester. Isotope exchange kinetics
showed that the heterodimer followed a pseudo-ordered mechanism with ATP
the leading and NEDD8 the trailing substrate. Ala72 of NEDD8 was
critical in binding APPBP1-UBA3. Bohnsack and Haas (2003) concluded that
the mechanism of NEDD8 activation by APPBP1-UBA3 shows a high degree of
conservation with ubiquitin activation by UBA1.
Huang et al. (2007) reported the structural analysis of a trapped
ubiquitin-like protein (UBL) activation complex for the human NEDD8
pathway containing NEDD8's heterodimeric E1 (APPBP1-UBA3), 2 NEDD8s (1
thioester-linked to E1, 1 noncovalently associated for adenylation), a
catalytically inactive E2 (UBC12), and MgATP. The results suggested that
a thioester switch toggles E1-E2 affinities. Two E2 binding sites depend
on NEDD8 being thioester-linked to E1. One is unmasked by a striking E1
conformational change. The other comes directly from the thioester-bound
NEDD8. After NEDD8 transfer to E2, reversion to an alternate E1
conformation would facilitate release of the covalent E2-NEDD8 thioester
product. Thus, Huang et al. (2007) concluded that transferring the UBL's
thioester linkage between successive conjugation enzymes can induce
conformational changes and alter interaction networks to drive
consecutive steps in UBL cascades.
*FIELD* RF
1. Bohnsack, R. N.; Haas, A. L.: Conservation in the mechanism of
Nedd8 activation by the human AppBp1-Uba3 heterodimer. J. Biol. Chem. 278:
26823-26830, 2003.
2. Chen, Y.; McPhie, D. L.; Hirschberg, J.; Neve, R. L.: The amyloid
precursor protein-binding protein APP-BP1 drives the cell cycle through
the S-M checkpoint and causes apoptosis in neurons. J. Biol. Chem. 275:
8929-8935, 2000.
3. Chow, N.; Korenberg, J. R.; Chen, X.-N.; Neve, R. L.: APP-BP1,
a novel protein that binds to the carboxyl-terminal region of the
amyloid precursor protein. J. Biol. Chem. 271: 11339-11346, 1996.
4. Huang, D. T.; Hung, H. W.; Zhuang, M.; Ohi, M. D.; Holton, J. M.;
Schulman, B. A.: Basis for a ubiquitin-like protein thioester switch
toggling E1-E2 affinity. Nature 445: 394-398, 2007.
5. Osaka, F.; Kawasaki, H.; Aida, N.; Saeki, M.; Chiba, T.; Kawashima,
S.; Tanaka, K.; Kato, S.: A new NEDD8-ligating system for cullin-4A. Genes
Dev. 12: 2263-2268, 1998.
6. Soucy, T. A.; Smith, P. G.; Milhollen, M. A.; Berger, A. J.; Gavin,
J. M.; Adhikari, S.; Brownell, J. E.; Burke, K. E.; Cardin, D. P.;
Critchley, S.; Cullis, C. A.; Doucette, A.; and 23 others: An inhibitor
of NEDD8-activating enzyme as a new approach to treat cancer. Nature 458:
732-736, 2009.
7. Walden, H.; Podgorski, M. S.; Schulman, B. A.: Insights into the
ubiquitin transfer cascade from the structure of the activating enzyme
for NEDD8. Nature 422: 330-334, 2003.
*FIELD* CN
Patricia A. Hartz - updated: 8/28/2009
Ada Hamosh - updated: 4/28/2009
Ada Hamosh - updated: 2/23/2007
Ada Hamosh - updated: 4/1/2003
*FIELD* CD
Sheryl A. Jankowski: 12/24/1998
*FIELD* ED
mgross: 09/08/2009
mgross: 9/8/2009
terry: 8/28/2009
alopez: 5/5/2009
terry: 4/28/2009
wwang: 12/17/2008
alopez: 3/2/2007
terry: 2/23/2007
carol: 5/12/2004
alopez: 4/1/2003
terry: 4/1/2003
psherman: 1/12/1999
psherman: 1/4/1999
*RECORD*
*FIELD* NO
603385
*FIELD* TI
*603385 NEDD8-ACTIVATING ENZYME E1, SUBUNIT 1; NAE1
;;AMYLOID BETA PRECURSOR PROTEIN-BINDING PROTEIN 1; APPBP1
read more*FIELD* TX
CLONING
Beta-amyloid precursor protein (APP; 104760) is a cell surface protein
that has structural features characteristic of cell surface receptors
with signal-transducing properties. To identify proteins with the
potential to bind and interact with APP, Chow et al. (1996) used a
C-terminal fragment of APP to screen a human fetal brain cDNA expression
library. They isolated cDNAs encoding an APP-binding protein, which they
designated APPBP1. Chow et al. (1996) demonstrated that the deduced
534-amino acid, 59-kD APPBP1 protein interacts with the C-terminal
region of APP in in vitro binding assays and with full-length APP from
mammalian cells in immunoprecipitation assays. The APPBP1 protein is 39%
identical to the protein encoded by the Arabidopsis auxin resistance
gene AXR1; both proteins are relatives of ubiquitin-activating enzyme-1
(UBE1; 314370). Northern blot analysis of human tissues revealed that
the single-copy APPBP1 gene is ubiquitously expressed as a 1.8-kb
transcript. In situ hybridization histochemistry showed that Appbp1 mRNA
is expressed throughout the rat brain.
MAPPING
Chow et al. (1996) localized the APPBP1 gene to 16q22 by fluorescence in
situ hybridization.
GENE FUNCTION
Ubiquitin (191339) is covalently attached to target proteins by a
multienzymatic system consisting of E1 (ubiquitin-activating), E2
(ubiquitin-conjugating), and E3 (ubiquitin-ligating) enzymes. Osaka et
al. (1998) found that NEDD8 (603171), a ubiquitin-like protein, is
conjugated to proteins in a manner analogous to ubiquitylation. They
found that APPBP1 can bind to NEDD8 in rabbit reticulocyte lysates.
However, since APPBP1 shows similarity to only the N-terminal domain of
an E1 enzyme, the authors reasoned that it must interact with a protein
showing similarity to the C-terminal region of E1s. By searching
sequence databases, Osaka et al. (1998) identified cDNAs encoding UBA3
(603172), the human homolog of yeast Uba3. In vitro, UBA3 formed a
complex with APPBP1 and a thioester linkage with NEDD8. Osaka et al.
(1998) suggested that the APPBP1/UBA3 complex functions as an E1-like
enzyme for the activation of NEDD8.
Ts41 mutant Chinese hamster cells show a temperature-sensitive defect in
the cell cycle and undergo successive S phases without intervening G2,
M, and G1 phases. The phenotype suggests that the mutated gene
negatively regulates entry into S phase and positively regulates entry
into mitosis. Chen et al. (2000) showed that human APPBP1 corrected the
ts41 defect. Overexpression of human APPBP1 in rat primary cortical
neurons caused apoptosis, and this effect required the UBA3-binding
domain of APPBP1. Dominant-negative human UBA3 and UBC12 (UBE2M; 603173)
mutants inhibited the ability of APPBP1 to cause apoptosis, implicating
the NEDD8 conjugation pathway. In addition, a specific caspase-6 (CASP6;
601532) inhibitor blocked APPBP1-induced apoptosis.
Walden et al. (2003) reported the structure and mutational analysis of
human APPBP1-UBA3, the heterodimeric E1 enzyme for NEDD8. Each E1
activity is specified by a domain: an adenylation domain resembling
bacterial adenylating enzymes, an E1-specific domain organized around
the catalytic cysteine, and a domain involved in E2 recognition
resembling ubiquitin. The domains are arranged around 2 clefts that
coordinate protein and nucleotide binding so that each of E1's reactions
drives the next, in an assembly-line fashion.
NEDD8 is first activated by an E1 enzyme, NEDD8-activating enzyme (NAE,
a heterodimer of NAE1 and UBA3 subunits), transferred to an E2 enzyme
(UBE2M), and then conjugated to target substrates. The NAE controls the
activity of the cullin-RING subtype of ubiquitin ligases, thereby
regulating the turnover of a subset of proteins upstream of the
proteasome. Substrates of cullin-RING ligases have important roles in
cellular processes associated with cancer cell growth and survival
pathways. Soucy et al. (2009) described MLN4924, a potent and selective
inhibitor of NAE. MLN4924 disrupts cullin-RING ligase-mediated protein
turnover leading to apoptotic death in human tumor cells by a novel
mechanism of action, the deregulation of S-phase DNA synthesis. MLN4924
suppressed the growth of human tumor xenografts in mice at compound
exposures that were well tolerated. Soucy et al. (2009) concluded that
NAE inhibitors may hold promise for the treatment of cancer.
BIOCHEMICAL FEATURES
Bohnsack and Haas (2003) purified APPBP1-UBA3 from human erythrocytes
and analyzed the kinetics of NEDD8 activation. In the presence of
radiolabeled ATP and radiolabeled recombinant NEDD8, APPBP1-UBA3 rapidly
formed a stable stoichiometric ternary complex composed of tightly bound
NEDD8 adenylate and UBA3-NEDD8 thiol ester. Isotope exchange kinetics
showed that the heterodimer followed a pseudo-ordered mechanism with ATP
the leading and NEDD8 the trailing substrate. Ala72 of NEDD8 was
critical in binding APPBP1-UBA3. Bohnsack and Haas (2003) concluded that
the mechanism of NEDD8 activation by APPBP1-UBA3 shows a high degree of
conservation with ubiquitin activation by UBA1.
Huang et al. (2007) reported the structural analysis of a trapped
ubiquitin-like protein (UBL) activation complex for the human NEDD8
pathway containing NEDD8's heterodimeric E1 (APPBP1-UBA3), 2 NEDD8s (1
thioester-linked to E1, 1 noncovalently associated for adenylation), a
catalytically inactive E2 (UBC12), and MgATP. The results suggested that
a thioester switch toggles E1-E2 affinities. Two E2 binding sites depend
on NEDD8 being thioester-linked to E1. One is unmasked by a striking E1
conformational change. The other comes directly from the thioester-bound
NEDD8. After NEDD8 transfer to E2, reversion to an alternate E1
conformation would facilitate release of the covalent E2-NEDD8 thioester
product. Thus, Huang et al. (2007) concluded that transferring the UBL's
thioester linkage between successive conjugation enzymes can induce
conformational changes and alter interaction networks to drive
consecutive steps in UBL cascades.
*FIELD* RF
1. Bohnsack, R. N.; Haas, A. L.: Conservation in the mechanism of
Nedd8 activation by the human AppBp1-Uba3 heterodimer. J. Biol. Chem. 278:
26823-26830, 2003.
2. Chen, Y.; McPhie, D. L.; Hirschberg, J.; Neve, R. L.: The amyloid
precursor protein-binding protein APP-BP1 drives the cell cycle through
the S-M checkpoint and causes apoptosis in neurons. J. Biol. Chem. 275:
8929-8935, 2000.
3. Chow, N.; Korenberg, J. R.; Chen, X.-N.; Neve, R. L.: APP-BP1,
a novel protein that binds to the carboxyl-terminal region of the
amyloid precursor protein. J. Biol. Chem. 271: 11339-11346, 1996.
4. Huang, D. T.; Hung, H. W.; Zhuang, M.; Ohi, M. D.; Holton, J. M.;
Schulman, B. A.: Basis for a ubiquitin-like protein thioester switch
toggling E1-E2 affinity. Nature 445: 394-398, 2007.
5. Osaka, F.; Kawasaki, H.; Aida, N.; Saeki, M.; Chiba, T.; Kawashima,
S.; Tanaka, K.; Kato, S.: A new NEDD8-ligating system for cullin-4A. Genes
Dev. 12: 2263-2268, 1998.
6. Soucy, T. A.; Smith, P. G.; Milhollen, M. A.; Berger, A. J.; Gavin,
J. M.; Adhikari, S.; Brownell, J. E.; Burke, K. E.; Cardin, D. P.;
Critchley, S.; Cullis, C. A.; Doucette, A.; and 23 others: An inhibitor
of NEDD8-activating enzyme as a new approach to treat cancer. Nature 458:
732-736, 2009.
7. Walden, H.; Podgorski, M. S.; Schulman, B. A.: Insights into the
ubiquitin transfer cascade from the structure of the activating enzyme
for NEDD8. Nature 422: 330-334, 2003.
*FIELD* CN
Patricia A. Hartz - updated: 8/28/2009
Ada Hamosh - updated: 4/28/2009
Ada Hamosh - updated: 2/23/2007
Ada Hamosh - updated: 4/1/2003
*FIELD* CD
Sheryl A. Jankowski: 12/24/1998
*FIELD* ED
mgross: 09/08/2009
mgross: 9/8/2009
terry: 8/28/2009
alopez: 5/5/2009
terry: 4/28/2009
wwang: 12/17/2008
alopez: 3/2/2007
terry: 2/23/2007
carol: 5/12/2004
alopez: 4/1/2003
terry: 4/1/2003
psherman: 1/12/1999
psherman: 1/4/1999