Full text data of METAP2
METAP2
(MNPEP, P67EIF2)
[Confidence: low (only semi-automatic identification from reviews)]
Methionine aminopeptidase 2; MAP 2; MetAP 2; 3.4.11.18 (Initiation factor 2-associated 67 kDa glycoprotein; p67; p67eIF2; Peptidase M)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Methionine aminopeptidase 2; MAP 2; MetAP 2; 3.4.11.18 (Initiation factor 2-associated 67 kDa glycoprotein; p67; p67eIF2; Peptidase M)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P50579
ID MAP2_HUMAN Reviewed; 478 AA.
AC P50579; B2RDI8;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1996, sequence version 1.
DT 22-JAN-2014, entry version 141.
DE RecName: Full=Methionine aminopeptidase 2;
DE Short=MAP 2;
DE Short=MetAP 2;
DE EC=3.4.11.18;
DE AltName: Full=Initiation factor 2-associated 67 kDa glycoprotein;
DE Short=p67;
DE Short=p67eIF2;
DE AltName: Full=Peptidase M;
GN Name=METAP2; Synonyms=MNPEP, P67EIF2;
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].
RC TISSUE=Brain;
RX PubMed=7644482; DOI=10.1073/pnas.92.17.7714;
RA Arfin S.M., Kendall R.L., Hall L., Weaver L.H., Stewart A.E.,
RA Matthews B.W., Bradshaw R.A.;
RT "Eukaryotic methionyl aminopeptidases: two classes of cobalt-dependent
RT enzymes.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:7714-7718(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=7873610; DOI=10.1016/0167-4781(94)00227-T;
RA Li X., Chang Y.;
RT "Molecular cloning of a human complementary DNA encoding an initiation
RT factor 2-associated protein (p67).";
RL Biochim. Biophys. Acta 1260:333-336(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
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].
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lymph;
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 [6]
RP FUNCTION IN EIF2S1 PROTECTION, AND GLYCOSYLATION.
RX PubMed=2511207;
RA Datta B., Ray M.K., Chakrabarti D., Wylie D.E., Gupta N.K.;
RT "Glycosylation of eukaryotic peptide chain initiation factor 2 (eIF-
RT 2)-associated 67-kDa polypeptide (p67) and its possible role in the
RT inhibition of eIF-2 kinase-catalyzed phosphorylation of the eIF-2
RT alpha-subunit.";
RL J. Biol. Chem. 264:20620-20624(1989).
RN [7]
RP COFACTOR.
RX PubMed=12718546; DOI=10.1021/bi020670c;
RA Wang J., Sheppard G.S., Lou P., Kawai M., Park C., Egan D.A.,
RA Schneider A., Bouska J., Lesniewski R., Henkin J.;
RT "Physiologically relevant metal cofactor for methionine
RT aminopeptidase-2 is manganese.";
RL Biochemistry 42:5035-5042(2003).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-45; SER-60; SER-63 AND
RP SER-74, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [9]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [10]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=20521764; DOI=10.1021/bi1005464;
RA Xiao Q., Zhang F., Nacev B.A., Liu J.O., Pei D.;
RT "Protein N-terminal processing: substrate specificity of Escherichia
RT coli and human methionine aminopeptidases.";
RL Biochemistry 49:5588-5599(2010).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-45 AND SER-74, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [12]
RP SUBCELLULAR LOCATION.
RX PubMed=21537465; DOI=10.4331/wjbc.v1.i10.313;
RA Wu S.;
RT "Localization and function of a eukaryotic-initiation-factor-2-
RT associated 67-kDa glycoprotein.";
RL World J. Biol. Chem. 1:313-320(2010).
RN [13]
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 [14]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) IN COMPLEX WITH FUMAGILLIN, AND
RP COFACTOR.
RX PubMed=9812898; DOI=10.1126/science.282.5392.1324;
RA Liu S., Widom J., Kemp C.W., Crews C.M., Clardy J.;
RT "Structure of human methionine aminopeptidase-2 complexed with
RT fumagillin.";
RL Science 282:1324-1327(1998).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) IN COMPLEX WITH COBALT IONS AND
RP BENGAMIDE, AND FUNCTION.
RX PubMed=14534293; DOI=10.1074/jbc.M309039200;
RA Towbin H., Bair K.W., DeCaprio J.A., Eck M.J., Kim S., Kinder F.R.,
RA Morollo A., Mueller D.R., Schindler P., Song H.K., van Oostrum J.,
RA Versace R.W., Voshol H., Wood J., Zabludoff S., Phillips P.E.;
RT "Proteomics-based target identification: bengamides as a new class of
RT methionine aminopeptidase inhibitors.";
RL J. Biol. Chem. 278:52964-52971(2003).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 110-478 IN COMPLEX WITH
RP INHIBITOR A-357300.
RX PubMed=15012983; DOI=10.1016/j.bmcl.2003.12.031;
RA Sheppard G.S., Wang J., Kawai M., BaMaung N.Y., Craig R.A.,
RA Erickson S.A., Lynch L., Patel J., Yang F., Searle X.B., Lou P.,
RA Park C., Kim K.H., Henkin J., Lesniewski R.;
RT "3-amino-2-hydroxyamides and related compounds as inhibitors of
RT methionine aminopeptidase-2.";
RL Bioorg. Med. Chem. Lett. 14:865-868(2004).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 110-478 IN COMPLEX WITH
RP 4-ARYL-1,2,3-TRIAZOLE AND COBALT IONS.
RX PubMed=16134930; DOI=10.1021/jm050408c;
RA Kallander L.S., Lu Q., Chen W., Tomaszek T., Yang G., Tew D.,
RA Meek T.D., Hofmann G.A., Schulz-Pritchard C.K., Smith W.W.,
RA Janson C.A., Ryan M.D., Zhang G.-F., Johanson K.O., Kirkpatrick R.B.,
RA Ho T.F., Fisher P.W., Mattern M.R., Johnson R.K., Hansbury M.J.,
RA Winkler J.D., Ward K.W., Veber D.F., Thompson S.K.;
RT "4-aryl-1,2,3-triazole: a novel template for a reversible methionine
RT aminopeptidase 2 inhibitor, optimized to inhibit angiogenesis in
RT vivo.";
RL J. Med. Chem. 48:5644-5647(2005).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) IN COMPLEXES WITH ZINC IONS AND
RP METHIONINE, AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=16540317; DOI=10.1016/j.bmcl.2006.02.047;
RA Nonato M.C., Widom J., Clardy J.;
RT "Human methionine aminopeptidase type 2 in complex with L- and D-
RT methionine.";
RL Bioorg. Med. Chem. Lett. 16:2580-2583(2006).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.35 ANGSTROMS) OF 110-478 IN COMPLEX WITH
RP MANGANESE AND INHIBITOR.
RX PubMed=17350258; DOI=10.1016/j.bmcl.2007.02.062;
RA Wang G.T., Mantei R.A., Kawai M., Tedrow J.S., Barnes D.M., Wang J.,
RA Zhang Q., Lou P., Garcia L.A., Bouska J., Yates M., Park C.,
RA Judge R.A., Lesniewski R., Sheppard G.S., Bell R.L.;
RT "Lead optimization of methionine aminopeptidase-2 (MetAP2) inhibitors
RT containing sulfonamides of 5,6-disubstituted anthranilic acids.";
RL Bioorg. Med. Chem. Lett. 17:2817-2822(2007).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 110-478 IN COMPLEX WITH
RP COBALT IONS AND INHIBITOR, COFACTOR, AND FUNCTION.
RX PubMed=17636946; DOI=10.1021/jm061182w;
RA Marino J.P. Jr., Fisher P.W., Hofmann G.A., Kirkpatrick R.B.,
RA Janson C.A., Johnson R.K., Ma C., Mattern M., Meek T.D., Ryan M.D.,
RA Schulz C., Smith W.W., Tew D.G., Tomazek T.A. Jr., Veber D.F.,
RA Xiong W.C., Yamamoto Y., Yamashita K., Yang G., Thompson S.K.;
RT "Highly potent inhibitors of methionine aminopeptidase-2 based on a
RT 1,2,4-triazole pharmacophore.";
RL J. Med. Chem. 50:3777-3785(2007).
CC -!- FUNCTION: Cotranslationally removes the N-terminal methionine from
CC nascent proteins. The N-terminal methionine is often cleaved when
CC the second residue in the primary sequence is small and uncharged
CC (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). The catalytic
CC activity of human METAP2 toward Met-Val peptides is consistently
CC two orders of magnitude higher than that of METAP1, suggesting
CC that it is responsible for processing proteins containing N-
CC terminal Met-Val and Met-Thr sequences in vivo.
CC -!- FUNCTION: Protects eukaryotic initiation factor EIF2S1 from
CC translation-inhibiting phosphorylation by inhibitory kinases such
CC as EIF2AK2/PKR and EIF2AK1/HCR. Plays a critical role in the
CC regulation of protein synthesis.
CC -!- CATALYTIC ACTIVITY: Release of N-terminal amino acids,
CC preferentially methionine, from peptides and arylamides.
CC -!- COFACTOR: Binds 2 divalent metal cations per subunit. Has a high-
CC affinity and a low affinity metal-binding site. The true nature of
CC the physiological cofactor is under debate. The enzyme is active
CC with cobalt, zinc, manganese or divalent iron ions. Most likely,
CC methionine aminopeptidases function as mononuclear Fe(2+)-
CC metalloproteases under physiological conditions, and the
CC catalytically relevant metal-binding site has been assigned to the
CC histidine-containing high-affinity site (By similarity). Also
CC manganese has been proposed to be the physiological cofactor for
CC human METAP2.
CC -!- SUBUNIT: Interacts strongly with the eIF-2 gamma-subunit EIF2S3
CC (By similarity). Binds EIF2S1 at low magnesium concentrations.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Note=About 30% of expressed
CC METAP2 associates with polysomes.
CC -!- PTM: Contains approximately 12 O-linked N-acetylglucosamine
CC (GlcNAc) residues. O-glycosylation is required for EIF2S1 binding.
CC -!- SIMILARITY: Belongs to the peptidase M24A family. Methionine
CC aminopeptidase eukaryotic type 2 subfamily.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/METAP2ID46053ch12q22.html";
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DR EMBL; U29607; AAA82930.1; -; mRNA.
DR EMBL; U13261; AAC63402.1; -; mRNA.
DR EMBL; AK315559; BAG37935.1; -; mRNA.
DR EMBL; CH471054; EAW97537.1; -; Genomic_DNA.
DR EMBL; BC013782; AAH13782.1; -; mRNA.
DR PIR; S52112; DPHUM2.
DR RefSeq; NP_006829.1; NM_006838.3.
DR UniGene; Hs.444986; -.
DR PDB; 1B59; X-ray; 1.80 A; A=109-478.
DR PDB; 1B6A; X-ray; 1.60 A; A=1-478.
DR PDB; 1BN5; X-ray; 1.80 A; A=1-478.
DR PDB; 1BOA; X-ray; 1.80 A; A=1-478.
DR PDB; 1KQ0; X-ray; 2.00 A; A=1-478.
DR PDB; 1KQ9; X-ray; 1.90 A; A=1-478.
DR PDB; 1QZY; X-ray; 1.60 A; A=1-478.
DR PDB; 1R58; X-ray; 1.90 A; A=110-478.
DR PDB; 1R5G; X-ray; 2.00 A; A=110-478.
DR PDB; 1R5H; X-ray; 2.40 A; A=110-478.
DR PDB; 1YW7; X-ray; 1.85 A; A=110-478.
DR PDB; 1YW8; X-ray; 2.65 A; A=110-478.
DR PDB; 1YW9; X-ray; 1.64 A; A=110-478.
DR PDB; 2ADU; X-ray; 1.90 A; A=110-478.
DR PDB; 2EA2; X-ray; 2.50 A; A=110-478.
DR PDB; 2EA4; X-ray; 2.35 A; A=110-478.
DR PDB; 2GA2; X-ray; 1.95 A; A=110-478.
DR PDB; 2OAZ; X-ray; 1.90 A; A=110-478.
DR PDBsum; 1B59; -.
DR PDBsum; 1B6A; -.
DR PDBsum; 1BN5; -.
DR PDBsum; 1BOA; -.
DR PDBsum; 1KQ0; -.
DR PDBsum; 1KQ9; -.
DR PDBsum; 1QZY; -.
DR PDBsum; 1R58; -.
DR PDBsum; 1R5G; -.
DR PDBsum; 1R5H; -.
DR PDBsum; 1YW7; -.
DR PDBsum; 1YW8; -.
DR PDBsum; 1YW9; -.
DR PDBsum; 2ADU; -.
DR PDBsum; 2EA2; -.
DR PDBsum; 2EA4; -.
DR PDBsum; 2GA2; -.
DR PDBsum; 2OAZ; -.
DR ProteinModelPortal; P50579; -.
DR SMR; P50579; 110-478.
DR IntAct; P50579; 2.
DR MINT; MINT-2803706; -.
DR STRING; 9606.ENSP00000325312; -.
DR BindingDB; P50579; -.
DR ChEMBL; CHEMBL3922; -.
DR DrugBank; DB00134; L-Methionine.
DR GuidetoPHARMACOLOGY; 1573; -.
DR MEROPS; M24.002; -.
DR PhosphoSite; P50579; -.
DR DMDM; 1703273; -.
DR REPRODUCTION-2DPAGE; IPI00033036; -.
DR PaxDb; P50579; -.
DR PeptideAtlas; P50579; -.
DR PRIDE; P50579; -.
DR DNASU; 10988; -.
DR Ensembl; ENST00000323666; ENSP00000325312; ENSG00000111142.
DR GeneID; 10988; -.
DR KEGG; hsa:10988; -.
DR UCSC; uc001tec.3; human.
DR CTD; 10988; -.
DR GeneCards; GC12P095800; -.
DR HGNC; HGNC:16672; METAP2.
DR HPA; CAB013025; -.
DR HPA; HPA019095; -.
DR MIM; 601870; gene.
DR neXtProt; NX_P50579; -.
DR PharmGKB; PA30765; -.
DR eggNOG; COG0024; -.
DR HOGENOM; HOG000226278; -.
DR HOVERGEN; HBG050495; -.
DR InParanoid; P50579; -.
DR KO; K01265; -.
DR OMA; IQICEEL; -.
DR PhylomeDB; P50579; -.
DR BRENDA; 3.4.11.18; 2681.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR ChiTaRS; METAP2; human.
DR EvolutionaryTrace; P50579; -.
DR GeneWiki; METAP2; -.
DR GenomeRNAi; 10988; -.
DR NextBio; 41747; -.
DR PRO; PR:P50579; -.
DR ArrayExpress; P50579; -.
DR Bgee; P50579; -.
DR CleanEx; HS_METAP2; -.
DR Genevestigator; P50579; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0004177; F:aminopeptidase activity; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-HAMAP.
DR GO; GO:0070006; F:metalloaminopeptidase activity; IEA:UniProtKB-HAMAP.
DR GO; GO:0008235; F:metalloexopeptidase activity; IDA:UniProtKB.
DR GO; GO:0031365; P:N-terminal protein amino acid modification; IDA:HGNC.
DR GO; GO:0018206; P:peptidyl-methionine modification; IDA:HGNC.
DR GO; GO:0070084; P:protein initiator methionine removal; IEA:UniProtKB-HAMAP.
DR GO; GO:0016485; P:protein processing; IDA:HGNC.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR GO; GO:0022400; P:regulation of rhodopsin mediated signaling pathway; TAS:Reactome.
DR GO; GO:0016056; P:rhodopsin mediated signaling pathway; TAS:Reactome.
DR Gene3D; 1.10.10.10; -; 1.
DR Gene3D; 3.90.230.10; -; 2.
DR HAMAP; MF_03175; MetAP_2_euk; 1; -.
DR InterPro; IPR001714; Pept_M24_MAP.
DR InterPro; IPR000994; Pept_M24_structural-domain.
DR InterPro; IPR002468; Pept_M24A_MAP2.
DR InterPro; IPR018349; Pept_M24A_MAP2_BS.
DR InterPro; IPR011991; WHTH_DNA-bd_dom.
DR PANTHER; PTHR10804:SF9; PTHR10804:SF9; 1.
DR Pfam; PF00557; Peptidase_M24; 1.
DR PRINTS; PR00599; MAPEPTIDASE.
DR SUPFAM; SSF55920; SSF55920; 2.
DR TIGRFAMs; TIGR00501; met_pdase_II; 1.
DR PROSITE; PS01202; MAP_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Aminopeptidase; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Glycoprotein; Hydrolase;
KW Metal-binding; Phosphoprotein; Protease; Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 478 Methionine aminopeptidase 2.
FT /FTId=PRO_0000148982.
FT COMPBIAS 41 46 Poly-Lys.
FT COMPBIAS 98 106 Poly-Lys.
FT METAL 251 251 Divalent metal cation 1.
FT METAL 262 262 Divalent metal cation 1.
FT METAL 262 262 Divalent metal cation 2; catalytic.
FT METAL 331 331 Divalent metal cation 2; catalytic; via
FT tele nitrogen.
FT METAL 364 364 Divalent metal cation 2; catalytic.
FT METAL 459 459 Divalent metal cation 1.
FT METAL 459 459 Divalent metal cation 2; catalytic.
FT BINDING 231 231 Substrate.
FT BINDING 339 339 Substrate.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 45 45 Phosphoserine.
FT MOD_RES 60 60 Phosphoserine; alternate.
FT MOD_RES 63 63 Phosphoserine; alternate.
FT MOD_RES 74 74 Phosphoserine.
FT CARBOHYD 60 60 O-linked (GlcNAc); alternate (By
FT similarity).
FT CARBOHYD 63 63 O-linked (GlcNAc); alternate (By
FT similarity).
FT HELIX 120 123
FT STRAND 133 135
FT STRAND 141 143
FT HELIX 149 151
FT HELIX 154 161
FT HELIX 163 186
FT HELIX 193 208
FT TURN 212 214
FT STRAND 215 225
FT STRAND 228 230
FT STRAND 248 256
FT STRAND 259 267
FT HELIX 271 273
FT HELIX 274 290
FT HELIX 297 309
FT STRAND 312 315
FT STRAND 318 321
FT STRAND 329 334
FT STRAND 337 339
FT STRAND 343 349
FT STRAND 360 370
FT STRAND 382 385
FT HELIX 397 409
FT TURN 410 412
FT HELIX 417 422
FT HELIX 429 437
FT STRAND 440 444
FT STRAND 455 464
FT STRAND 469 471
SQ SEQUENCE 478 AA; 52892 MW; 5788E4BB83E48F9A CRC64;
MAGVEEVAAS GSHLNGDLDP DDREEGAAST AEEAAKKKRR KKKKSKGPSA AGEQEPDKES
GASVDEVARQ LERSALEDKE RDEDDEDGDG DGDGATGKKK KKKKKKRGPK VQTDPPSVPI
CDLYPNGVFP KGQECEYPPT QDGRTAAWRT TSEEKKALDQ ASEEIWNDFR EAAEAHRQVR
KYVMSWIKPG MTMIEICEKL EDCSRKLIKE NGLNAGLAFP TGCSLNNCAA HYTPNAGDTT
VLQYDDICKI DFGTHISGRI IDCAFTVTFN PKYDTLLKAV KDATNTGIKC AGIDVRLCDV
GEAIQEVMES YEVEIDGKTY QVKPIRNLNG HSIGQYRIHA GKTVPIVKGG EATRMEEGEV
YAIETFGSTG KGVVHDDMEC SHYMKNFDVG HVPIRLPRTK HLLNVINENF GTLAFCRRWL
DRLGESKYLM ALKNLCDLGI VDPYPPLCDI KGSYTAQFEH TILLRPTCKE VVSRGDDY
//
ID MAP2_HUMAN Reviewed; 478 AA.
AC P50579; B2RDI8;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1996, sequence version 1.
DT 22-JAN-2014, entry version 141.
DE RecName: Full=Methionine aminopeptidase 2;
DE Short=MAP 2;
DE Short=MetAP 2;
DE EC=3.4.11.18;
DE AltName: Full=Initiation factor 2-associated 67 kDa glycoprotein;
DE Short=p67;
DE Short=p67eIF2;
DE AltName: Full=Peptidase M;
GN Name=METAP2; Synonyms=MNPEP, P67EIF2;
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].
RC TISSUE=Brain;
RX PubMed=7644482; DOI=10.1073/pnas.92.17.7714;
RA Arfin S.M., Kendall R.L., Hall L., Weaver L.H., Stewart A.E.,
RA Matthews B.W., Bradshaw R.A.;
RT "Eukaryotic methionyl aminopeptidases: two classes of cobalt-dependent
RT enzymes.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:7714-7718(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=7873610; DOI=10.1016/0167-4781(94)00227-T;
RA Li X., Chang Y.;
RT "Molecular cloning of a human complementary DNA encoding an initiation
RT factor 2-associated protein (p67).";
RL Biochim. Biophys. Acta 1260:333-336(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
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].
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lymph;
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 [6]
RP FUNCTION IN EIF2S1 PROTECTION, AND GLYCOSYLATION.
RX PubMed=2511207;
RA Datta B., Ray M.K., Chakrabarti D., Wylie D.E., Gupta N.K.;
RT "Glycosylation of eukaryotic peptide chain initiation factor 2 (eIF-
RT 2)-associated 67-kDa polypeptide (p67) and its possible role in the
RT inhibition of eIF-2 kinase-catalyzed phosphorylation of the eIF-2
RT alpha-subunit.";
RL J. Biol. Chem. 264:20620-20624(1989).
RN [7]
RP COFACTOR.
RX PubMed=12718546; DOI=10.1021/bi020670c;
RA Wang J., Sheppard G.S., Lou P., Kawai M., Park C., Egan D.A.,
RA Schneider A., Bouska J., Lesniewski R., Henkin J.;
RT "Physiologically relevant metal cofactor for methionine
RT aminopeptidase-2 is manganese.";
RL Biochemistry 42:5035-5042(2003).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-45; SER-60; SER-63 AND
RP SER-74, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [9]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [10]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=20521764; DOI=10.1021/bi1005464;
RA Xiao Q., Zhang F., Nacev B.A., Liu J.O., Pei D.;
RT "Protein N-terminal processing: substrate specificity of Escherichia
RT coli and human methionine aminopeptidases.";
RL Biochemistry 49:5588-5599(2010).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-45 AND SER-74, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [12]
RP SUBCELLULAR LOCATION.
RX PubMed=21537465; DOI=10.4331/wjbc.v1.i10.313;
RA Wu S.;
RT "Localization and function of a eukaryotic-initiation-factor-2-
RT associated 67-kDa glycoprotein.";
RL World J. Biol. Chem. 1:313-320(2010).
RN [13]
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 [14]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) IN COMPLEX WITH FUMAGILLIN, AND
RP COFACTOR.
RX PubMed=9812898; DOI=10.1126/science.282.5392.1324;
RA Liu S., Widom J., Kemp C.W., Crews C.M., Clardy J.;
RT "Structure of human methionine aminopeptidase-2 complexed with
RT fumagillin.";
RL Science 282:1324-1327(1998).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) IN COMPLEX WITH COBALT IONS AND
RP BENGAMIDE, AND FUNCTION.
RX PubMed=14534293; DOI=10.1074/jbc.M309039200;
RA Towbin H., Bair K.W., DeCaprio J.A., Eck M.J., Kim S., Kinder F.R.,
RA Morollo A., Mueller D.R., Schindler P., Song H.K., van Oostrum J.,
RA Versace R.W., Voshol H., Wood J., Zabludoff S., Phillips P.E.;
RT "Proteomics-based target identification: bengamides as a new class of
RT methionine aminopeptidase inhibitors.";
RL J. Biol. Chem. 278:52964-52971(2003).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 110-478 IN COMPLEX WITH
RP INHIBITOR A-357300.
RX PubMed=15012983; DOI=10.1016/j.bmcl.2003.12.031;
RA Sheppard G.S., Wang J., Kawai M., BaMaung N.Y., Craig R.A.,
RA Erickson S.A., Lynch L., Patel J., Yang F., Searle X.B., Lou P.,
RA Park C., Kim K.H., Henkin J., Lesniewski R.;
RT "3-amino-2-hydroxyamides and related compounds as inhibitors of
RT methionine aminopeptidase-2.";
RL Bioorg. Med. Chem. Lett. 14:865-868(2004).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 110-478 IN COMPLEX WITH
RP 4-ARYL-1,2,3-TRIAZOLE AND COBALT IONS.
RX PubMed=16134930; DOI=10.1021/jm050408c;
RA Kallander L.S., Lu Q., Chen W., Tomaszek T., Yang G., Tew D.,
RA Meek T.D., Hofmann G.A., Schulz-Pritchard C.K., Smith W.W.,
RA Janson C.A., Ryan M.D., Zhang G.-F., Johanson K.O., Kirkpatrick R.B.,
RA Ho T.F., Fisher P.W., Mattern M.R., Johnson R.K., Hansbury M.J.,
RA Winkler J.D., Ward K.W., Veber D.F., Thompson S.K.;
RT "4-aryl-1,2,3-triazole: a novel template for a reversible methionine
RT aminopeptidase 2 inhibitor, optimized to inhibit angiogenesis in
RT vivo.";
RL J. Med. Chem. 48:5644-5647(2005).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) IN COMPLEXES WITH ZINC IONS AND
RP METHIONINE, AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=16540317; DOI=10.1016/j.bmcl.2006.02.047;
RA Nonato M.C., Widom J., Clardy J.;
RT "Human methionine aminopeptidase type 2 in complex with L- and D-
RT methionine.";
RL Bioorg. Med. Chem. Lett. 16:2580-2583(2006).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.35 ANGSTROMS) OF 110-478 IN COMPLEX WITH
RP MANGANESE AND INHIBITOR.
RX PubMed=17350258; DOI=10.1016/j.bmcl.2007.02.062;
RA Wang G.T., Mantei R.A., Kawai M., Tedrow J.S., Barnes D.M., Wang J.,
RA Zhang Q., Lou P., Garcia L.A., Bouska J., Yates M., Park C.,
RA Judge R.A., Lesniewski R., Sheppard G.S., Bell R.L.;
RT "Lead optimization of methionine aminopeptidase-2 (MetAP2) inhibitors
RT containing sulfonamides of 5,6-disubstituted anthranilic acids.";
RL Bioorg. Med. Chem. Lett. 17:2817-2822(2007).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 110-478 IN COMPLEX WITH
RP COBALT IONS AND INHIBITOR, COFACTOR, AND FUNCTION.
RX PubMed=17636946; DOI=10.1021/jm061182w;
RA Marino J.P. Jr., Fisher P.W., Hofmann G.A., Kirkpatrick R.B.,
RA Janson C.A., Johnson R.K., Ma C., Mattern M., Meek T.D., Ryan M.D.,
RA Schulz C., Smith W.W., Tew D.G., Tomazek T.A. Jr., Veber D.F.,
RA Xiong W.C., Yamamoto Y., Yamashita K., Yang G., Thompson S.K.;
RT "Highly potent inhibitors of methionine aminopeptidase-2 based on a
RT 1,2,4-triazole pharmacophore.";
RL J. Med. Chem. 50:3777-3785(2007).
CC -!- FUNCTION: Cotranslationally removes the N-terminal methionine from
CC nascent proteins. The N-terminal methionine is often cleaved when
CC the second residue in the primary sequence is small and uncharged
CC (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). The catalytic
CC activity of human METAP2 toward Met-Val peptides is consistently
CC two orders of magnitude higher than that of METAP1, suggesting
CC that it is responsible for processing proteins containing N-
CC terminal Met-Val and Met-Thr sequences in vivo.
CC -!- FUNCTION: Protects eukaryotic initiation factor EIF2S1 from
CC translation-inhibiting phosphorylation by inhibitory kinases such
CC as EIF2AK2/PKR and EIF2AK1/HCR. Plays a critical role in the
CC regulation of protein synthesis.
CC -!- CATALYTIC ACTIVITY: Release of N-terminal amino acids,
CC preferentially methionine, from peptides and arylamides.
CC -!- COFACTOR: Binds 2 divalent metal cations per subunit. Has a high-
CC affinity and a low affinity metal-binding site. The true nature of
CC the physiological cofactor is under debate. The enzyme is active
CC with cobalt, zinc, manganese or divalent iron ions. Most likely,
CC methionine aminopeptidases function as mononuclear Fe(2+)-
CC metalloproteases under physiological conditions, and the
CC catalytically relevant metal-binding site has been assigned to the
CC histidine-containing high-affinity site (By similarity). Also
CC manganese has been proposed to be the physiological cofactor for
CC human METAP2.
CC -!- SUBUNIT: Interacts strongly with the eIF-2 gamma-subunit EIF2S3
CC (By similarity). Binds EIF2S1 at low magnesium concentrations.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Note=About 30% of expressed
CC METAP2 associates with polysomes.
CC -!- PTM: Contains approximately 12 O-linked N-acetylglucosamine
CC (GlcNAc) residues. O-glycosylation is required for EIF2S1 binding.
CC -!- SIMILARITY: Belongs to the peptidase M24A family. Methionine
CC aminopeptidase eukaryotic type 2 subfamily.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/METAP2ID46053ch12q22.html";
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DR EMBL; U29607; AAA82930.1; -; mRNA.
DR EMBL; U13261; AAC63402.1; -; mRNA.
DR EMBL; AK315559; BAG37935.1; -; mRNA.
DR EMBL; CH471054; EAW97537.1; -; Genomic_DNA.
DR EMBL; BC013782; AAH13782.1; -; mRNA.
DR PIR; S52112; DPHUM2.
DR RefSeq; NP_006829.1; NM_006838.3.
DR UniGene; Hs.444986; -.
DR PDB; 1B59; X-ray; 1.80 A; A=109-478.
DR PDB; 1B6A; X-ray; 1.60 A; A=1-478.
DR PDB; 1BN5; X-ray; 1.80 A; A=1-478.
DR PDB; 1BOA; X-ray; 1.80 A; A=1-478.
DR PDB; 1KQ0; X-ray; 2.00 A; A=1-478.
DR PDB; 1KQ9; X-ray; 1.90 A; A=1-478.
DR PDB; 1QZY; X-ray; 1.60 A; A=1-478.
DR PDB; 1R58; X-ray; 1.90 A; A=110-478.
DR PDB; 1R5G; X-ray; 2.00 A; A=110-478.
DR PDB; 1R5H; X-ray; 2.40 A; A=110-478.
DR PDB; 1YW7; X-ray; 1.85 A; A=110-478.
DR PDB; 1YW8; X-ray; 2.65 A; A=110-478.
DR PDB; 1YW9; X-ray; 1.64 A; A=110-478.
DR PDB; 2ADU; X-ray; 1.90 A; A=110-478.
DR PDB; 2EA2; X-ray; 2.50 A; A=110-478.
DR PDB; 2EA4; X-ray; 2.35 A; A=110-478.
DR PDB; 2GA2; X-ray; 1.95 A; A=110-478.
DR PDB; 2OAZ; X-ray; 1.90 A; A=110-478.
DR PDBsum; 1B59; -.
DR PDBsum; 1B6A; -.
DR PDBsum; 1BN5; -.
DR PDBsum; 1BOA; -.
DR PDBsum; 1KQ0; -.
DR PDBsum; 1KQ9; -.
DR PDBsum; 1QZY; -.
DR PDBsum; 1R58; -.
DR PDBsum; 1R5G; -.
DR PDBsum; 1R5H; -.
DR PDBsum; 1YW7; -.
DR PDBsum; 1YW8; -.
DR PDBsum; 1YW9; -.
DR PDBsum; 2ADU; -.
DR PDBsum; 2EA2; -.
DR PDBsum; 2EA4; -.
DR PDBsum; 2GA2; -.
DR PDBsum; 2OAZ; -.
DR ProteinModelPortal; P50579; -.
DR SMR; P50579; 110-478.
DR IntAct; P50579; 2.
DR MINT; MINT-2803706; -.
DR STRING; 9606.ENSP00000325312; -.
DR BindingDB; P50579; -.
DR ChEMBL; CHEMBL3922; -.
DR DrugBank; DB00134; L-Methionine.
DR GuidetoPHARMACOLOGY; 1573; -.
DR MEROPS; M24.002; -.
DR PhosphoSite; P50579; -.
DR DMDM; 1703273; -.
DR REPRODUCTION-2DPAGE; IPI00033036; -.
DR PaxDb; P50579; -.
DR PeptideAtlas; P50579; -.
DR PRIDE; P50579; -.
DR DNASU; 10988; -.
DR Ensembl; ENST00000323666; ENSP00000325312; ENSG00000111142.
DR GeneID; 10988; -.
DR KEGG; hsa:10988; -.
DR UCSC; uc001tec.3; human.
DR CTD; 10988; -.
DR GeneCards; GC12P095800; -.
DR HGNC; HGNC:16672; METAP2.
DR HPA; CAB013025; -.
DR HPA; HPA019095; -.
DR MIM; 601870; gene.
DR neXtProt; NX_P50579; -.
DR PharmGKB; PA30765; -.
DR eggNOG; COG0024; -.
DR HOGENOM; HOG000226278; -.
DR HOVERGEN; HBG050495; -.
DR InParanoid; P50579; -.
DR KO; K01265; -.
DR OMA; IQICEEL; -.
DR PhylomeDB; P50579; -.
DR BRENDA; 3.4.11.18; 2681.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR ChiTaRS; METAP2; human.
DR EvolutionaryTrace; P50579; -.
DR GeneWiki; METAP2; -.
DR GenomeRNAi; 10988; -.
DR NextBio; 41747; -.
DR PRO; PR:P50579; -.
DR ArrayExpress; P50579; -.
DR Bgee; P50579; -.
DR CleanEx; HS_METAP2; -.
DR Genevestigator; P50579; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0004177; F:aminopeptidase activity; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-HAMAP.
DR GO; GO:0070006; F:metalloaminopeptidase activity; IEA:UniProtKB-HAMAP.
DR GO; GO:0008235; F:metalloexopeptidase activity; IDA:UniProtKB.
DR GO; GO:0031365; P:N-terminal protein amino acid modification; IDA:HGNC.
DR GO; GO:0018206; P:peptidyl-methionine modification; IDA:HGNC.
DR GO; GO:0070084; P:protein initiator methionine removal; IEA:UniProtKB-HAMAP.
DR GO; GO:0016485; P:protein processing; IDA:HGNC.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR GO; GO:0022400; P:regulation of rhodopsin mediated signaling pathway; TAS:Reactome.
DR GO; GO:0016056; P:rhodopsin mediated signaling pathway; TAS:Reactome.
DR Gene3D; 1.10.10.10; -; 1.
DR Gene3D; 3.90.230.10; -; 2.
DR HAMAP; MF_03175; MetAP_2_euk; 1; -.
DR InterPro; IPR001714; Pept_M24_MAP.
DR InterPro; IPR000994; Pept_M24_structural-domain.
DR InterPro; IPR002468; Pept_M24A_MAP2.
DR InterPro; IPR018349; Pept_M24A_MAP2_BS.
DR InterPro; IPR011991; WHTH_DNA-bd_dom.
DR PANTHER; PTHR10804:SF9; PTHR10804:SF9; 1.
DR Pfam; PF00557; Peptidase_M24; 1.
DR PRINTS; PR00599; MAPEPTIDASE.
DR SUPFAM; SSF55920; SSF55920; 2.
DR TIGRFAMs; TIGR00501; met_pdase_II; 1.
DR PROSITE; PS01202; MAP_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Aminopeptidase; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Glycoprotein; Hydrolase;
KW Metal-binding; Phosphoprotein; Protease; Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 478 Methionine aminopeptidase 2.
FT /FTId=PRO_0000148982.
FT COMPBIAS 41 46 Poly-Lys.
FT COMPBIAS 98 106 Poly-Lys.
FT METAL 251 251 Divalent metal cation 1.
FT METAL 262 262 Divalent metal cation 1.
FT METAL 262 262 Divalent metal cation 2; catalytic.
FT METAL 331 331 Divalent metal cation 2; catalytic; via
FT tele nitrogen.
FT METAL 364 364 Divalent metal cation 2; catalytic.
FT METAL 459 459 Divalent metal cation 1.
FT METAL 459 459 Divalent metal cation 2; catalytic.
FT BINDING 231 231 Substrate.
FT BINDING 339 339 Substrate.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 45 45 Phosphoserine.
FT MOD_RES 60 60 Phosphoserine; alternate.
FT MOD_RES 63 63 Phosphoserine; alternate.
FT MOD_RES 74 74 Phosphoserine.
FT CARBOHYD 60 60 O-linked (GlcNAc); alternate (By
FT similarity).
FT CARBOHYD 63 63 O-linked (GlcNAc); alternate (By
FT similarity).
FT HELIX 120 123
FT STRAND 133 135
FT STRAND 141 143
FT HELIX 149 151
FT HELIX 154 161
FT HELIX 163 186
FT HELIX 193 208
FT TURN 212 214
FT STRAND 215 225
FT STRAND 228 230
FT STRAND 248 256
FT STRAND 259 267
FT HELIX 271 273
FT HELIX 274 290
FT HELIX 297 309
FT STRAND 312 315
FT STRAND 318 321
FT STRAND 329 334
FT STRAND 337 339
FT STRAND 343 349
FT STRAND 360 370
FT STRAND 382 385
FT HELIX 397 409
FT TURN 410 412
FT HELIX 417 422
FT HELIX 429 437
FT STRAND 440 444
FT STRAND 455 464
FT STRAND 469 471
SQ SEQUENCE 478 AA; 52892 MW; 5788E4BB83E48F9A CRC64;
MAGVEEVAAS GSHLNGDLDP DDREEGAAST AEEAAKKKRR KKKKSKGPSA AGEQEPDKES
GASVDEVARQ LERSALEDKE RDEDDEDGDG DGDGATGKKK KKKKKKRGPK VQTDPPSVPI
CDLYPNGVFP KGQECEYPPT QDGRTAAWRT TSEEKKALDQ ASEEIWNDFR EAAEAHRQVR
KYVMSWIKPG MTMIEICEKL EDCSRKLIKE NGLNAGLAFP TGCSLNNCAA HYTPNAGDTT
VLQYDDICKI DFGTHISGRI IDCAFTVTFN PKYDTLLKAV KDATNTGIKC AGIDVRLCDV
GEAIQEVMES YEVEIDGKTY QVKPIRNLNG HSIGQYRIHA GKTVPIVKGG EATRMEEGEV
YAIETFGSTG KGVVHDDMEC SHYMKNFDVG HVPIRLPRTK HLLNVINENF GTLAFCRRWL
DRLGESKYLM ALKNLCDLGI VDPYPPLCDI KGSYTAQFEH TILLRPTCKE VVSRGDDY
//
MIM
601870
*RECORD*
*FIELD* NO
601870
*FIELD* TI
*601870 METHIONINE AMINOPEPTIDASE 2; METAP2
;;EUKARYOTIC INITIATION FACTOR 2-ASSOCIATED PROTEIN, 67-KD;;
read morep67
*FIELD* TX
Wu et al. (1993) isolated a 67-kD protein, termed p67, which bound to
eukaryotic initiation factor-2 (eIF-2). They demonstrated that p67
protects eIF-2-alpha from phosphorylation by eIF-2 kinases and thus
promotes protein synthesis in the cell. During heme or serum
deprivation, p67 is degraded and protein synthesis is inhibited; on the
other hand, after addition of a mitogen to serum-starved cells, p67
appears at a high level with an accompanying increase in protein
synthesis. The authors suggested that p67 may play a critical role in
the regulation of protein synthesis.
Wu et al. (1993) cloned the cDNA corresponding to rat p67. Sequence
analysis revealed that the rat gene encodes a 480-amino acid
polypeptide. Based on the sequence of rat p67, Li and Chang (1995)
cloned the human p67 homolog. Sequence analysis showed that the human
gene encodes a 478-amino acid polypeptide that shares 92% identity with
rat p67. Northern blot analysis revealed that human p67 is expressed as
a 2.1-kb transcript in all tissues tested. Interestingly, Li and Chang
(1995) noted that human p67 shares approximately 22% identity with yeast
and bacterial methionine aminopeptidases (MetAPs). Li and Chang (1996)
purified human p67 and demonstrated that it has methionine
aminopeptidase activity. Furthermore, they showed that its kinetic
parameters, substrate specificity, and cobalt dependence are similar to
those of other MetAPs. The authors suggested that human p67 may have
dual functions: regulation of protein synthesis via interaction with
eIF-2, and N-terminal protein processing.
The inhibition of new blood vessel formation (angiogenesis) is an
effective means of limiting both the size and metastasis of solid
tumors. One of the leading angiogenic compounds, fumagillin and its
derivative TNP-470, inhibits neovascularization via endothelial cell
cycle arrest in the late G1 phase. Because TNP-470 proved to be
effective in in vitro and animal model studies, phase III antitumor
clinical trials were initiated. To investigate the molecular mode of
action of TNP-470, Sin et al. (1997) used a derivative of the TNP-470
parent compound, the fungal metabolite fumagillin, and purified a
mammalian protein from bovine brain lysate that is selectively and
covalently bound by this natural product. This fumagillin binding
protein was found to be a metalloprotease, methionine aminopeptidase-2
(MetAP2), which is highly conserved between human and Saccharomyces
cerevisiae. In the absence of MetAP1, a distantly related methionine
aminopeptidase, MetAP2 function is essential for vegetative growth in
yeast. Sin et al. (1997) demonstrated that fumagillin selectively
inhibits the S. cerevisiae MetAP2 protein in vivo. The binding is highly
specific as judged by the failure of fumagillin to inhibit MetAP1 in
vivo. Sin et al. (1997) recognized the identity of the methionine
aminopeptidase-2, which selectively binds fumagillin, to the p67 cloned
and characterized by Wu et al. (1993).
Fumagillin and ovalicin are structurally related natural products that
potently inhibit angiogenesis by blocking endothelial cell
proliferation. To determine the structural elements of these inhibitors
and methionine aminopeptidase-2 (EC 3.4.11.18) that are involved in this
interaction, Griffith et al. (1998) studied various fumagillin analogs
with structural changes. Their results suggested that fumagillin and
ovalicin inhibit MetAP2 by irreversible blockage of the active site.
*FIELD* RF
1. Griffith, E. C.; Su, Z.; Niwayama, S.; Ramsay, C. A.; Chang, Y-
H.; Liu, J. O.: Molecular recognition of angiogenesis inhibitors
fumagillin and ovalicin by methionine aminopeptidase 2. Proc. Nat.
Acad. Sci. 95: 15183-15188, 1998.
2. Li, X.; Chang, Y.-H.: Molecular cloning of a human complementary
DNA encoding an initiation factor 2-associated protein (p-67). Biochim.
Biophys. Acta 1260: 333-336, 1995.
3. Li, X.; Chang, Y.-H.: Evidence that the human homologue of a rat
initiation factor-2 associated protein (p-67) is a methionine aminopeptidase. Biochem.
Biophys. Res. Commun. 227: 152-159, 1996.
4. Sin, N.; Meng, L.; Wang, M. Q. W.; Wen, J. J.; Bornmann, W. G.;
Crews, C. M.: The anti-angiogenic agent fumagillin covalently binds
and inhibits the methionine aminopeptidase, MetAP-2. Proc. Nat. Acad.
Sci. 94: 6099-6103, 1997.
5. Wu, S.; Gupta, S.; Chatterjee, N.; Hileman, R. E.; Kinzy, T. G.;
Denslow, N. D.; Merrick, W. C.; Chakrabarti, D.; Osterman, J. C.;
Gupta, N. K.: Cloning and characterization of complementary DNA encoding
the eukaryotic initiation factor 2-associated 67-kDa protein (p-67). J.
Biol. Chem. 268: 10796-10801, 1993.
*FIELD* CN
Victor A. McKusick - updated: 3/1/1999
*FIELD* CD
Jennifer P. Macke: 6/13/1997
*FIELD* ED
carol: 07/22/2006
carol: 3/22/1999
terry: 3/1/1999
carol: 6/22/1998
alopez: 7/16/1997
*RECORD*
*FIELD* NO
601870
*FIELD* TI
*601870 METHIONINE AMINOPEPTIDASE 2; METAP2
;;EUKARYOTIC INITIATION FACTOR 2-ASSOCIATED PROTEIN, 67-KD;;
read morep67
*FIELD* TX
Wu et al. (1993) isolated a 67-kD protein, termed p67, which bound to
eukaryotic initiation factor-2 (eIF-2). They demonstrated that p67
protects eIF-2-alpha from phosphorylation by eIF-2 kinases and thus
promotes protein synthesis in the cell. During heme or serum
deprivation, p67 is degraded and protein synthesis is inhibited; on the
other hand, after addition of a mitogen to serum-starved cells, p67
appears at a high level with an accompanying increase in protein
synthesis. The authors suggested that p67 may play a critical role in
the regulation of protein synthesis.
Wu et al. (1993) cloned the cDNA corresponding to rat p67. Sequence
analysis revealed that the rat gene encodes a 480-amino acid
polypeptide. Based on the sequence of rat p67, Li and Chang (1995)
cloned the human p67 homolog. Sequence analysis showed that the human
gene encodes a 478-amino acid polypeptide that shares 92% identity with
rat p67. Northern blot analysis revealed that human p67 is expressed as
a 2.1-kb transcript in all tissues tested. Interestingly, Li and Chang
(1995) noted that human p67 shares approximately 22% identity with yeast
and bacterial methionine aminopeptidases (MetAPs). Li and Chang (1996)
purified human p67 and demonstrated that it has methionine
aminopeptidase activity. Furthermore, they showed that its kinetic
parameters, substrate specificity, and cobalt dependence are similar to
those of other MetAPs. The authors suggested that human p67 may have
dual functions: regulation of protein synthesis via interaction with
eIF-2, and N-terminal protein processing.
The inhibition of new blood vessel formation (angiogenesis) is an
effective means of limiting both the size and metastasis of solid
tumors. One of the leading angiogenic compounds, fumagillin and its
derivative TNP-470, inhibits neovascularization via endothelial cell
cycle arrest in the late G1 phase. Because TNP-470 proved to be
effective in in vitro and animal model studies, phase III antitumor
clinical trials were initiated. To investigate the molecular mode of
action of TNP-470, Sin et al. (1997) used a derivative of the TNP-470
parent compound, the fungal metabolite fumagillin, and purified a
mammalian protein from bovine brain lysate that is selectively and
covalently bound by this natural product. This fumagillin binding
protein was found to be a metalloprotease, methionine aminopeptidase-2
(MetAP2), which is highly conserved between human and Saccharomyces
cerevisiae. In the absence of MetAP1, a distantly related methionine
aminopeptidase, MetAP2 function is essential for vegetative growth in
yeast. Sin et al. (1997) demonstrated that fumagillin selectively
inhibits the S. cerevisiae MetAP2 protein in vivo. The binding is highly
specific as judged by the failure of fumagillin to inhibit MetAP1 in
vivo. Sin et al. (1997) recognized the identity of the methionine
aminopeptidase-2, which selectively binds fumagillin, to the p67 cloned
and characterized by Wu et al. (1993).
Fumagillin and ovalicin are structurally related natural products that
potently inhibit angiogenesis by blocking endothelial cell
proliferation. To determine the structural elements of these inhibitors
and methionine aminopeptidase-2 (EC 3.4.11.18) that are involved in this
interaction, Griffith et al. (1998) studied various fumagillin analogs
with structural changes. Their results suggested that fumagillin and
ovalicin inhibit MetAP2 by irreversible blockage of the active site.
*FIELD* RF
1. Griffith, E. C.; Su, Z.; Niwayama, S.; Ramsay, C. A.; Chang, Y-
H.; Liu, J. O.: Molecular recognition of angiogenesis inhibitors
fumagillin and ovalicin by methionine aminopeptidase 2. Proc. Nat.
Acad. Sci. 95: 15183-15188, 1998.
2. Li, X.; Chang, Y.-H.: Molecular cloning of a human complementary
DNA encoding an initiation factor 2-associated protein (p-67). Biochim.
Biophys. Acta 1260: 333-336, 1995.
3. Li, X.; Chang, Y.-H.: Evidence that the human homologue of a rat
initiation factor-2 associated protein (p-67) is a methionine aminopeptidase. Biochem.
Biophys. Res. Commun. 227: 152-159, 1996.
4. Sin, N.; Meng, L.; Wang, M. Q. W.; Wen, J. J.; Bornmann, W. G.;
Crews, C. M.: The anti-angiogenic agent fumagillin covalently binds
and inhibits the methionine aminopeptidase, MetAP-2. Proc. Nat. Acad.
Sci. 94: 6099-6103, 1997.
5. Wu, S.; Gupta, S.; Chatterjee, N.; Hileman, R. E.; Kinzy, T. G.;
Denslow, N. D.; Merrick, W. C.; Chakrabarti, D.; Osterman, J. C.;
Gupta, N. K.: Cloning and characterization of complementary DNA encoding
the eukaryotic initiation factor 2-associated 67-kDa protein (p-67). J.
Biol. Chem. 268: 10796-10801, 1993.
*FIELD* CN
Victor A. McKusick - updated: 3/1/1999
*FIELD* CD
Jennifer P. Macke: 6/13/1997
*FIELD* ED
carol: 07/22/2006
carol: 3/22/1999
terry: 3/1/1999
carol: 6/22/1998
alopez: 7/16/1997