ID BACE2_HUMAN Reviewed; 518 AA. AC Q9Y5Z0; A8K7P1; Q5DIH8; Q8N2D4; Q9H2V8; Q9NZL1; Q9NZL2; Q9UJT6; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1999, sequence version 1. DT 27-MAR-2024, entry version 207. DE RecName: Full=Beta-secretase 2; DE EC=3.4.23.45 {ECO:0000269|PubMed:21907142}; DE AltName: Full=Aspartic-like protease 56 kDa; DE AltName: Full=Aspartyl protease 1; DE Short=ASP1; DE Short=Asp 1; DE AltName: Full=Beta-site amyloid precursor protein cleaving enzyme 2; DE Short=Beta-site APP cleaving enzyme 2; DE AltName: Full=Down region aspartic protease; DE Short=DRAP; DE AltName: Full=Memapsin-1; DE AltName: Full=Membrane-associated aspartic protease 1; DE AltName: Full=Theta-secretase; DE Flags: Precursor; GN Name=BACE2; Synonyms=AEPLC, ALP56, ASP21; GN ORFNames=CDA13, UNQ418/PRO852; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF N-TERMINUS, RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=10591213; DOI=10.1038/990107; RA Yan R., Bienkowski M.J., Shuck M.E., Miao H., Tory M.C., Pauley A.M., RA Brashier J.R., Stratman N.C., Mathews W.R., Buhl A.E., Carter D.B., RA Tomasselli A.G., Parodi L.A., Heinrikson R.L., Gurney M.E.; RT "Membrane-anchored aspartyl protease with Alzheimer's disease beta- RT secretase activity."; RL Nature 402:533-537(1999). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AUTOCATALYTIC CLEAVAGE, INDUCTION, RP TISSUE SPECIFICITY, AND MUTAGENESIS OF ASP-110 AND ASP-303. RC TISSUE=Bone marrow; RX PubMed=10838186; DOI=10.1016/s0925-4439(00)00014-4; RA Xin H., Stephans J.C., Duan X., Harrowe G., Kim E., Grieshammer U., RA Kingsley C., Giese K.; RT "Identification of a novel aspartic-like protease differentially expressed RT in human breast cancer cell lines."; RL Biochim. Biophys. Acta 1501:125-137(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3), AND TISSUE SPECIFICITY. RX PubMed=10965118; DOI=10.1159/000015608; RA Solans A., Estivill X., de La Luna S.; RT "A new aspartyl protease on 21q22.3, BACE2, is highly similar to RT Alzheimer's amyloid precursor protein beta-secretase."; RL Cytogenet. Cell Genet. 89:177-184(2000). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND RP GLYCOSYLATION. RX PubMed=10683441; DOI=10.1016/s0014-5793(00)01192-3; RA Acquati F., Accarino M.P., Nucci C., Fumagalli P., Jovine L., RA Ottolenghi S., Taramelli R.; RT "The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of RT the aspartic protease family, maps to the down critical region."; RL FEBS Lett. 468:59-64(2000). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY. RX PubMed=10749877; DOI=10.1074/jbc.m002688200; RA Bennett B.D., Babu-Khan S., Loeloff R., Louis J.-C., Curran E., Citron M., RA Vassar R.; RT "Expression analysis of BACE2 in brain and peripheral tissues."; RL J. Biol. Chem. 275:20647-20651(2000). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF N-TERMINUS, RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, GLYCOSYLATION, AND RP CATALYTIC ACTIVITY. RX PubMed=11083922; DOI=10.1006/mcne.2000.0884; RA Hussain I., Powell D.J., Howlett D.R., Chapman G.A., Gilmour L., RA Murdock P.R., Tew D.G., Meek T.D., Chapman C., Schneider K., RA Ratcliffe S.J., Tattersall D., Testa T.T., Southan C., Ryan D.M., RA Simmons D.L., Walsh F.S., Dingwall C., Christie G.; RT "ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase RT site."; RL Mol. Cell. Neurosci. 16:609-619(2000). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY. RX PubMed=10677483; DOI=10.1073/pnas.97.4.1456; RA Lin X., Koelsch G., Wu S., Downs D., Dashti A., Tang J.; RT "Human aspartic protease memapsin 2 cleaves the beta-secretase site of RT beta-amyloid precursor protein."; RL Proc. Natl. Acad. Sci. U.S.A. 97:1456-1460(2000). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4). RC TISSUE=Pheochromocytoma; RA Li Y., Huang Q., Peng Y., Song H., Yu Y., Xu S., Ren S., Chen Z., Han Z.; RL Submitted (DEC-1999) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RX PubMed=12975309; DOI=10.1101/gr.1293003; RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A., RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.; RT "The secreted protein discovery initiative (SPDI), a large-scale effort to RT identify novel human secreted and transmembrane proteins: a bioinformatics RT assessment."; RL Genome Res. 13:2265-2270(2003). RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 5). RC TISSUE=Ovary, and Stomach; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=10830953; DOI=10.1038/35012518; RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S., RA Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M., RA Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A., Menzel U., RA Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A., RA Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J., RA Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K., RA Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G., RA Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J., RA Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S., RA Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K., RA Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L.; RT "The DNA sequence of human chromosome 21."; RL Nature 405:311-319(2000). RN [12] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [13] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [14] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-47, AND FUNCTION. RX PubMed=15857888; DOI=10.1096/fj.04-3426com; RA Sun X., Wang Y., Qing H., Christensen M.A., Liu Y., Zhou W., Tong Y., RA Xiao C., Huang Y., Zhang S., Liu X., Song W.; RT "Distinct transcriptional regulation and function of the human BACE2 and RT BACE1 genes."; RL FASEB J. 19:739-749(2005). RN [15] RP PROTEIN SEQUENCE OF N-TERMINUS, AUTOCATALYTIC CLEAVAGE, FUNCTION, AND RP SUBCELLULAR LOCATION. RX PubMed=11423558; DOI=10.1074/jbc.m105583200; RA Yan R., Munzner J.B., Shuck M.E., Bienkowski M.J.; RT "BACE2 functions as an alternative alpha-secretase in cells."; RL J. Biol. Chem. 276:34019-34027(2001). RN [16] RP PROTEIN SEQUENCE OF N-TERMINUS, AND FUNCTION. RX PubMed=16816112; DOI=10.1096/fj.05-5632com; RA Sun X., He G., Song W.; RT "BACE2, as a novel APP theta-secretase, is not responsible for the RT pathogenesis of Alzheimer's disease in Down syndrome."; RL FASEB J. 20:1369-1376(2006). RN [17] RP PROTEIN SEQUENCE OF N-TERMINUS, X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF RP 78-460, SUBUNIT, AND DISULFIDE BONDS. RX PubMed=16305800; DOI=10.1016/j.jmb.2005.10.027; RA Ostermann N., Eder J., Eidhoff U., Zink F., Hassiepen U., Worpenberg S., RA Maibaum J., Simic O., Hommel U., Gerhartz B.; RT "Crystal structure of human BACE2 in complex with a hydroxyethylamine RT transition-state inhibitor."; RL J. Mol. Biol. 355:249-261(2006). RN [18] RP AUTOCATALYTIC CLEAVAGE, AND MUTAGENESIS OF ASP-110. RX PubMed=11316808; DOI=10.1074/jbc.m101069200; RA Hussain I., Christie G., Schneider K., Moore S., Dingwall C.; RT "Prodomain processing of Asp1 (BACE2) is autocatalytic."; RL J. Biol. Chem. 276:23322-23328(2001). RN [19] RP INTERACTION WITH RTN3 AND RTN4. RX PubMed=16965550; DOI=10.1111/j.1460-9568.2006.05005.x; RA Murayama K.S., Kametani F., Saito S., Kume H., Akiyama H., Araki W.; RT "Reticulons RTN3 and RTN4-B/C interact with BACE1 and inhibit its ability RT to produce amyloid beta-protein."; RL Eur. J. Neurosci. 24:1237-1244(2006). RN [20] RP SUBCELLULAR LOCATION, FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=21907142; DOI=10.1016/j.cmet.2011.06.018; RA Esterhazy D., Stuetzer I., Wang H., Rechsteiner M.P., Beauchamp J., RA Doebeli H., Hilpert H., Matile H., Prummer M., Schmidt A., Lieske N., RA Boehm B., Marselli L., Bosco D., Kerr-Conte J., Aebersold R., Spinas G.A., RA Moch H., Migliorini C., Stoffel M.; RT "Bace2 is a beta cell-enriched protease that regulates pancreatic beta cell RT function and mass."; RL Cell Metab. 14:365-377(2011). RN [21] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=23754390; DOI=10.1073/pnas.1220748110; RA Rochin L., Hurbain I., Serneels L., Fort C., Watt B., Leblanc P., RA Marks M.S., De Strooper B., Raposo G., van Niel G.; RT "BACE2 processes PMEL to form the melanosome amyloid matrix in pigment RT cells."; RL Proc. Natl. Acad. Sci. U.S.A. 110:10658-10663(2013). CC -!- FUNCTION: Responsible for the proteolytic processing of the amyloid CC precursor protein (APP). Cleaves APP, between residues 690 and 691, CC leading to the generation and extracellular release of beta-cleaved CC soluble APP, and a corresponding cell-associated C-terminal fragment CC which is later released by gamma-secretase. It has also been shown that CC it can cleave APP between residues 671 and 672 (PubMed:10591213, CC PubMed:11083922, PubMed:11423558, PubMed:15857888, PubMed:16816112). CC Involved in the proteolytic shedding of PMEL at early stages of CC melanosome biogenesis. Cleaves PMEL within the M-beta fragment to CC release the amyloidogenic PMEL luminal fragment containing M-alpha and CC a small portion of M-beta N-terminus. This is a prerequisite step for CC subsequent processing and assembly of PMEL fibrils into amyloid sheets CC (PubMed:23754390). Responsible also for the proteolytic processing of CC CLTRN in pancreatic beta cells (PubMed:21907142). CC {ECO:0000269|PubMed:10591213, ECO:0000269|PubMed:11083922, CC ECO:0000269|PubMed:11423558, ECO:0000269|PubMed:15857888, CC ECO:0000269|PubMed:16816112, ECO:0000269|PubMed:21907142, CC ECO:0000269|PubMed:23754390}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Broad endopeptidase specificity. Cleaves Glu-Val-Asn-Leu-|- CC Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid CC precursor protein.; EC=3.4.23.45; CC Evidence={ECO:0000269|PubMed:11083922, ECO:0000269|PubMed:21907142}; CC -!- SUBUNIT: Monomer. Interacts with RTN3 and RTN4. CC {ECO:0000269|PubMed:16305800, ECO:0000269|PubMed:16965550}. CC -!- INTERACTION: CC Q9Y5Z0; P05067: APP; NbExp=3; IntAct=EBI-11282723, EBI-77613; CC Q9Y5Z0; Q9NP61: ARFGAP3; NbExp=3; IntAct=EBI-11282723, EBI-2875816; CC Q9Y5Z0; Q13510-3: ASAH1; NbExp=3; IntAct=EBI-11282723, EBI-25917771; CC Q9Y5Z0; Q86XM0: CATSPERD; NbExp=3; IntAct=EBI-11282723, EBI-10260328; CC Q9Y5Z0; Q9Y6W6: DUSP10; NbExp=3; IntAct=EBI-11282723, EBI-3443946; CC Q9Y5Z0; P10997: IAPP; NbExp=3; IntAct=EBI-11282723, EBI-8526679; CC Q9Y5Z0; P57682: KLF3; NbExp=3; IntAct=EBI-11282723, EBI-8472267; CC Q9Y5Z0; P08727: KRT19; NbExp=3; IntAct=EBI-11282723, EBI-742756; CC Q9Y5Z0; Q92615: LARP4B; NbExp=3; IntAct=EBI-11282723, EBI-1052558; CC Q9Y5Z0; Q14847-2: LASP1; NbExp=3; IntAct=EBI-11282723, EBI-9088686; CC Q9Y5Z0; Q6DKI2: LGALS9C; NbExp=3; IntAct=EBI-11282723, EBI-9088829; CC Q9Y5Z0; P42679: MATK; NbExp=3; IntAct=EBI-11282723, EBI-751664; CC Q9Y5Z0; Q8WZ73-3: RFFL; NbExp=3; IntAct=EBI-11282723, EBI-25839575; CC Q9Y5Z0; Q9BSD3: RHNO1; NbExp=3; IntAct=EBI-11282723, EBI-9658624; CC Q9Y5Z0; Q9BY12-3: SCAPER; NbExp=3; IntAct=EBI-11282723, EBI-25837959; CC Q9Y5Z0; O75558: STX11; NbExp=3; IntAct=EBI-11282723, EBI-714135; CC Q9Y5Z0; Q8TDR4: TCP10L; NbExp=3; IntAct=EBI-11282723, EBI-3923210; CC Q9Y5Z0; Q9BXU0: TEX12; NbExp=3; IntAct=EBI-11282723, EBI-12090309; CC Q9Y5Z0; Q8IUR5-4: TMTC1; NbExp=3; IntAct=EBI-11282723, EBI-9089156; CC Q9Y5Z0; P06753-2: TPM3; NbExp=3; IntAct=EBI-11282723, EBI-10977875; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:21907142}; CC Single-pass type I membrane protein {ECO:0000255}. Golgi apparatus CC {ECO:0000269|PubMed:11423558}. Endoplasmic reticulum. Endosome. CC Melanosome {ECO:0000269|PubMed:23754390}. Note=Colocalizes with PMEL in CC stage I and II melanosomes. {ECO:0000269|PubMed:23754390}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=5; CC Name=1; Synonyms=Isoform A; CC IsoId=Q9Y5Z0-1; Sequence=Displayed; CC Name=2; Synonyms=Isoform C; CC IsoId=Q9Y5Z0-2; Sequence=VSP_038025; CC Name=3; Synonyms=Isoform B; CC IsoId=Q9Y5Z0-3; Sequence=VSP_038026, VSP_038027; CC Name=4; CC IsoId=Q9Y5Z0-4; Sequence=VSP_038024; CC Name=5; CC IsoId=Q9Y5Z0-5; Sequence=VSP_038023; CC -!- TISSUE SPECIFICITY: Brain. Present in neurons within the hippocampus, CC frontal cortex and temporal cortex (at protein level). Expressed at low CC levels in most peripheral tissues and at higher levels in colon, CC kidney, pancreas, placenta, prostate, stomach and trachea. Expressed at CC low levels in the brain. Found in spinal cord, medulla oblongata, CC substantia nigra and locus coruleus. Expressed in the ductal epithelium CC of both normal and malignant prostate. {ECO:0000269|PubMed:10591213, CC ECO:0000269|PubMed:10677483, ECO:0000269|PubMed:10683441, CC ECO:0000269|PubMed:10749877, ECO:0000269|PubMed:10838186, CC ECO:0000269|PubMed:10965118, ECO:0000269|PubMed:11083922}. CC -!- INDUCTION: Up-regulated in primary breast and colon tumors and liver CC metastasis. {ECO:0000269|PubMed:10838186}. CC -!- PTM: Undergoes autoproteolytic cleavage. {ECO:0000269|PubMed:11316808, CC ECO:0000269|PubMed:11423558}. CC -!- PTM: Glycosylated. {ECO:0000269|PubMed:10683441, CC ECO:0000269|PubMed:11083922}. CC -!- SIMILARITY: Belongs to the peptidase A1 family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF200342; AAF17078.1; -; mRNA. DR EMBL; AF117892; AAD45240.1; -; mRNA. DR EMBL; AF178532; AAF29494.1; -; mRNA. DR EMBL; AF188276; AAF35835.1; -; mRNA. DR EMBL; AF188277; AAF35836.1; -; mRNA. DR EMBL; AF050171; AAD45963.1; -; mRNA. DR EMBL; AF204944; AAF26368.1; -; mRNA. DR EMBL; AF200192; AAF13714.1; -; mRNA. DR EMBL; AF212252; AAG41783.1; -; mRNA. DR EMBL; AY358927; AAQ89286.1; -; mRNA. DR EMBL; AK075539; BAC11682.1; -; mRNA. DR EMBL; AK292056; BAF84745.1; -; mRNA. DR EMBL; AL163284; CAB90458.1; -; Genomic_DNA. DR EMBL; AL163285; CAB90554.1; -; Genomic_DNA. DR EMBL; CH471079; EAX09611.1; -; Genomic_DNA. DR EMBL; CH471079; EAX09613.1; -; Genomic_DNA. DR EMBL; BC014453; AAH14453.1; -; mRNA. DR EMBL; AY769996; AAX14808.1; -; Genomic_DNA. DR CCDS; CCDS13668.1; -. [Q9Y5Z0-1] DR CCDS; CCDS13669.1; -. [Q9Y5Z0-2] DR CCDS; CCDS13670.1; -. [Q9Y5Z0-3] DR RefSeq; NP_036237.2; NM_012105.4. [Q9Y5Z0-1] DR RefSeq; NP_620476.1; NM_138991.2. [Q9Y5Z0-2] DR RefSeq; NP_620477.1; NM_138992.2. [Q9Y5Z0-3] DR PDB; 2EWY; X-ray; 3.10 A; A/B/C/D=78-460. DR PDB; 3ZKG; X-ray; 1.90 A; A/B=75-460. DR PDB; 3ZKI; X-ray; 2.40 A; A/B=75-460. DR PDB; 3ZKM; X-ray; 1.85 A; A/B=75-460. DR PDB; 3ZKN; X-ray; 2.00 A; A/B=75-460. DR PDB; 3ZKQ; X-ray; 1.51 A; A=75-460. DR PDB; 3ZKS; X-ray; 2.11 A; A=75-460. DR PDB; 3ZKX; X-ray; 2.37 A; A=75-460. DR PDB; 3ZL7; X-ray; 3.20 A; A=75-460. DR PDB; 3ZLQ; X-ray; 2.10 A; A/B=75-460. DR PDB; 4BEL; X-ray; 1.85 A; A/B=75-460. DR PDB; 4BFB; X-ray; 2.21 A; A/B=75-460. DR PDB; 6JSZ; X-ray; 1.53 A; A=75-460. DR PDB; 6UJ0; X-ray; 2.15 A; A/B=1-460. DR PDB; 6UJ1; X-ray; 3.03 A; A/B=1-460. DR PDB; 7D5B; X-ray; 1.31 A; A=75-460. DR PDB; 7D5U; X-ray; 2.04 A; A=75-460. DR PDB; 7F1G; X-ray; 1.50 A; A=75-460. DR PDB; 7N4N; X-ray; 1.41 A; A=75-460. DR PDBsum; 2EWY; -. DR PDBsum; 3ZKG; -. DR PDBsum; 3ZKI; -. DR PDBsum; 3ZKM; -. DR PDBsum; 3ZKN; -. DR PDBsum; 3ZKQ; -. DR PDBsum; 3ZKS; -. DR PDBsum; 3ZKX; -. DR PDBsum; 3ZL7; -. DR PDBsum; 3ZLQ; -. DR PDBsum; 4BEL; -. DR PDBsum; 4BFB; -. DR PDBsum; 6JSZ; -. DR PDBsum; 6UJ0; -. DR PDBsum; 6UJ1; -. DR PDBsum; 7D5B; -. DR PDBsum; 7D5U; -. DR PDBsum; 7F1G; -. DR PDBsum; 7N4N; -. DR AlphaFoldDB; Q9Y5Z0; -. DR SMR; Q9Y5Z0; -. DR BioGRID; 117353; 101. DR IntAct; Q9Y5Z0; 41. DR MINT; Q9Y5Z0; -. DR STRING; 9606.ENSP00000332979; -. DR BindingDB; Q9Y5Z0; -. DR ChEMBL; CHEMBL2525; -. DR GuidetoPHARMACOLOGY; 2331; -. DR MEROPS; A01.041; -. DR TCDB; 8.A.32.1.2; the Beta-amyloid cleaving enzyme (bace1) family. DR GlyCosmos; Q9Y5Z0; 3 sites, 1 glycan. DR GlyGen; Q9Y5Z0; 5 sites, 2 O-linked glycans (3 sites). DR iPTMnet; Q9Y5Z0; -. DR PhosphoSitePlus; Q9Y5Z0; -. DR SwissPalm; Q9Y5Z0; -. DR BioMuta; BACE2; -. DR DMDM; 6685260; -. DR EPD; Q9Y5Z0; -. DR jPOST; Q9Y5Z0; -. DR MassIVE; Q9Y5Z0; -. DR MaxQB; Q9Y5Z0; -. DR PaxDb; 9606-ENSP00000332979; -. DR PeptideAtlas; Q9Y5Z0; -. DR ProteomicsDB; 86546; -. [Q9Y5Z0-1] DR ProteomicsDB; 86547; -. [Q9Y5Z0-2] DR ProteomicsDB; 86548; -. [Q9Y5Z0-3] DR ProteomicsDB; 86549; -. [Q9Y5Z0-4] DR ProteomicsDB; 86550; -. [Q9Y5Z0-5] DR Pumba; Q9Y5Z0; -. DR ABCD; Q9Y5Z0; 3 sequenced antibodies. DR Antibodypedia; 4410; 603 antibodies from 38 providers. DR DNASU; 25825; -. DR Ensembl; ENST00000328735.10; ENSP00000333854.6; ENSG00000182240.16. [Q9Y5Z0-3] DR Ensembl; ENST00000330333.11; ENSP00000332979.6; ENSG00000182240.16. [Q9Y5Z0-1] DR Ensembl; ENST00000347667.5; ENSP00000327528.4; ENSG00000182240.16. [Q9Y5Z0-2] DR GeneID; 25825; -. DR KEGG; hsa:25825; -. DR MANE-Select; ENST00000330333.11; ENSP00000332979.6; NM_012105.5; NP_036237.2. DR UCSC; uc002yyw.5; human. [Q9Y5Z0-1] DR AGR; HGNC:934; -. DR CTD; 25825; -. DR DisGeNET; 25825; -. DR GeneCards; BACE2; -. DR HGNC; HGNC:934; BACE2. DR HPA; ENSG00000182240; Tissue enhanced (salivary). DR MIM; 605668; gene. DR neXtProt; NX_Q9Y5Z0; -. DR OpenTargets; ENSG00000182240; -. DR PharmGKB; PA25233; -. DR VEuPathDB; HostDB:ENSG00000182240; -. DR eggNOG; KOG1339; Eukaryota. DR GeneTree; ENSGT00940000159548; -. DR HOGENOM; CLU_039009_0_0_1; -. DR InParanoid; Q9Y5Z0; -. DR OMA; KEWYYQV; -. DR OrthoDB; 603414at2759; -. DR PhylomeDB; Q9Y5Z0; -. DR TreeFam; TF329595; -. DR BioCyc; MetaCyc:G66-33964-MONOMER; -. DR BRENDA; 3.4.23.45; 2681. DR BRENDA; 3.4.24.56; 2681. DR PathwayCommons; Q9Y5Z0; -. DR SignaLink; Q9Y5Z0; -. DR SIGNOR; Q9Y5Z0; -. DR BioGRID-ORCS; 25825; 11 hits in 1151 CRISPR screens. DR ChiTaRS; BACE2; human. DR EvolutionaryTrace; Q9Y5Z0; -. DR GeneWiki; Beta-secretase_2; -. DR GenomeRNAi; 25825; -. DR Pharos; Q9Y5Z0; Tchem. DR PRO; PR:Q9Y5Z0; -. DR Proteomes; UP000005640; Chromosome 21. DR RNAct; Q9Y5Z0; Protein. DR Bgee; ENSG00000182240; Expressed in parotid gland and 182 other cell types or tissues. DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell. DR GO; GO:0005768; C:endosome; IBA:GO_Central. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0033162; C:melanosome membrane; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; NAS:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0005802; C:trans-Golgi network; IBA:GO_Central. DR GO; GO:0004190; F:aspartic-type endopeptidase activity; IDA:UniProtKB. DR GO; GO:0050435; P:amyloid-beta metabolic process; IBA:GO_Central. DR GO; GO:0042593; P:glucose homeostasis; IMP:UniProtKB. DR GO; GO:0032438; P:melanosome organization; IMP:UniProtKB. DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; IDA:UniProtKB. DR GO; GO:0042985; P:negative regulation of amyloid precursor protein biosynthetic process; IMP:UniProtKB. DR GO; GO:0016486; P:peptide hormone processing; NAS:UniProtKB. DR GO; GO:0016485; P:protein processing; IDA:UniProtKB. DR GO; GO:0006508; P:proteolysis; NAS:UniProtKB. DR CDD; cd05473; beta_secretase_like; 1. DR Gene3D; 2.40.70.10; Acid Proteases; 2. DR InterPro; IPR001461; Aspartic_peptidase_A1. DR InterPro; IPR001969; Aspartic_peptidase_AS. DR InterPro; IPR009119; BACE. DR InterPro; IPR009121; BACE2. DR InterPro; IPR033874; Memapsin-like. DR InterPro; IPR033121; PEPTIDASE_A1. DR InterPro; IPR021109; Peptidase_aspartic_dom_sf. DR PANTHER; PTHR47965; ASPARTYL PROTEASE-RELATED; 1. DR PANTHER; PTHR47965:SF40; BETA-SECRETASE 2; 1. DR Pfam; PF00026; Asp; 1. DR PRINTS; PR01817; BACE2. DR PRINTS; PR01815; BACEFAMILY. DR PRINTS; PR00792; PEPSIN. DR SUPFAM; SSF50630; Acid proteases; 1. DR PROSITE; PS00141; ASP_PROTEASE; 2. DR PROSITE; PS51767; PEPTIDASE_A1; 1. DR Genevisible; Q9Y5Z0; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Aspartyl protease; KW Autocatalytic cleavage; Cell membrane; Direct protein sequencing; KW Disulfide bond; Endoplasmic reticulum; Endosome; Glycoprotein; KW Golgi apparatus; Hydrolase; Membrane; Protease; Reference proteome; Signal; KW Transmembrane; Transmembrane helix; Zymogen. FT SIGNAL 1..20 FT /evidence="ECO:0000255" FT PROPEP 21..62 FT /evidence="ECO:0000269|PubMed:10591213, FT ECO:0000269|PubMed:11083922, ECO:0000269|PubMed:11423558, FT ECO:0000269|PubMed:16305800, ECO:0000269|PubMed:16816112" FT /id="PRO_0000025945" FT CHAIN 63..518 FT /note="Beta-secretase 2" FT /id="PRO_0000025946" FT TOPO_DOM 21..473 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 474..494 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 495..518 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 92..429 FT /note="Peptidase A1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01103" FT ACT_SITE 110 FT ACT_SITE 303 FT CARBOHYD 170 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 366 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 233..433 FT /evidence="ECO:0000269|PubMed:16305800" FT DISULFID 292..457 FT /evidence="ECO:0000269|PubMed:16305800" FT DISULFID 344..393 FT /evidence="ECO:0000269|PubMed:16305800" FT VAR_SEQ 1..95 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_038023" FT VAR_SEQ 1..79 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|Ref.8" FT /id="VSP_038024" FT VAR_SEQ 329..378 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:10965118" FT /id="VSP_038025" FT VAR_SEQ 379..396 FT /note="LYIQPMMGAGLNYECYRF -> KLQVLQCLKFPGLSQQRM (in isoform FT 3)" FT /evidence="ECO:0000303|PubMed:10965118" FT /id="VSP_038026" FT VAR_SEQ 397..518 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:10965118" FT /id="VSP_038027" FT MUTAGEN 110 FT /note="D->A,N: Loss of autoproteolytic cleavage." FT /evidence="ECO:0000269|PubMed:10838186, FT ECO:0000269|PubMed:11316808" FT MUTAGEN 303 FT /note="D->A: Loss of autoproteolytic cleavage." FT /evidence="ECO:0000269|PubMed:10838186" FT CONFLICT 36 FT /note="A -> T (in Ref. 7; AAF13714)" FT /evidence="ECO:0000305" FT CONFLICT 184 FT /note="E -> G (in Ref. 10; BAC11682)" FT /evidence="ECO:0000305" FT CONFLICT 192 FT /note="K -> Q (in Ref. 10; BAC11682)" FT /evidence="ECO:0000305" FT CONFLICT 233 FT /note="C -> R (in Ref. 10; BAC11682)" FT /evidence="ECO:0000305" FT HELIX 78..80 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 84..87 FT /evidence="ECO:0007829|PDB:7D5B" FT TURN 88..90 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 91..98 FT /evidence="ECO:0007829|PDB:7D5B" FT TURN 99..102 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 103..110 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 116..119 FT /evidence="ECO:0007829|PDB:7D5B" FT HELIX 132..134 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 139..149 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 152..164 FT /evidence="ECO:0007829|PDB:7D5B" FT TURN 166..168 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 173..185 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 194..198 FT /evidence="ECO:0007829|PDB:7D5B" FT HELIX 202..204 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 206..208 FT /evidence="ECO:0007829|PDB:6UJ1" FT HELIX 214..222 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 228..232 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 247..253 FT /evidence="ECO:0007829|PDB:7D5B" FT HELIX 256..258 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 264..270 FT /evidence="ECO:0007829|PDB:7D5B" FT TURN 271..274 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 278..283 FT /evidence="ECO:0007829|PDB:7D5B" FT HELIX 292..295 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 296..298 FT /evidence="ECO:0007829|PDB:6JSZ" FT STRAND 300..302 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 308..312 FT /evidence="ECO:0007829|PDB:7D5B" FT HELIX 313..326 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 328..330 FT /evidence="ECO:0007829|PDB:7D5B" FT HELIX 334..337 FT /evidence="ECO:0007829|PDB:7D5B" FT HELIX 339..342 FT /evidence="ECO:0007829|PDB:3ZKN" FT STRAND 343..345 FT /evidence="ECO:0007829|PDB:7N4N" FT HELIX 347..349 FT /evidence="ECO:0007829|PDB:4BFB" FT HELIX 352..354 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 358..363 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 369..375 FT /evidence="ECO:0007829|PDB:7D5B" FT HELIX 377..379 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 381..383 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 393..403 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 405..407 FT /evidence="ECO:0007829|PDB:7D5B" FT HELIX 409..412 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 415..420 FT /evidence="ECO:0007829|PDB:7D5B" FT TURN 421..424 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 425..430 FT /evidence="ECO:0007829|PDB:7D5B" FT HELIX 432..434 FT /evidence="ECO:0007829|PDB:6UJ0" FT HELIX 436..438 FT /evidence="ECO:0007829|PDB:6UJ1" FT STRAND 439..449 FT /evidence="ECO:0007829|PDB:7D5B" FT STRAND 451..453 FT /evidence="ECO:0007829|PDB:7F1G" FT CONFLICT Q9Y5Z0-3:381 FT /note="Q -> R (in Ref. 3; AAF35836)" FT /evidence="ECO:0000305" FT CONFLICT Q9Y5Z0-3:396 FT /note="M -> F (in Ref. 3; AAF35836)" FT /evidence="ECO:0000305" SQ SEQUENCE 518 AA; 56180 MW; 2E903150823760D3 CRC64; MGALARALLL PLLAQWLLRA APELAPAPFT LPLRVAAATN RVVAPTPGPG TPAERHADGL ALALEPALAS PAGAANFLAM VDNLQGDSGR GYYLEMLIGT PPQKLQILVD TGSSNFAVAG TPHSYIDTYF DTERSSTYRS KGFDVTVKYT QGSWTGFVGE DLVTIPKGFN TSFLVNIATI FESENFFLPG IKWNGILGLA YATLAKPSSS LETFFDSLVT QANIPNVFSM QMCGAGLPVA GSGTNGGSLV LGGIEPSLYK GDIWYTPIKE EWYYQIEILK LEIGGQSLNL DCREYNADKA IVDSGTTLLR LPQKVFDAVV EAVARASLIP EFSDGFWTGS QLACWTNSET PWSYFPKISI YLRDENSSRS FRITILPQLY IQPMMGAGLN YECYRFGISP STNALVIGAT VMEGFYVIFD RAQKRVGFAA SPCAEIAGAA VSEISGPFST EDVASNCVPA QSLSEPILWI VSYALMSVCG AILLVLIVLL LLPFRCQRRP RDPEVVNDES SLVRHRWK //