Beta-secretase 1

Details

Name
Beta-secretase 1
Synonyms
  • 3.4.23.46
  • Asp 2
  • ASP2
  • Aspartyl protease 2
  • BACE
  • Beta-site amyloid precursor protein cleaving enzyme 1
  • Beta-site APP cleaving enzyme 1
  • KIAA1149
  • Memapsin-2
  • Membrane-associated aspartic protease 2
Gene Name
BACE1
Organism
Humans
Amino acid sequence
>lcl|BSEQ0037109|Beta-secretase 1
MAQALPWLLLWMGAGVLPAHGTQHGIRLPLRSGLGGAPLGLRLPRETDEEPEEPGRRGSF
VEMVDNLRGKSGQGYYVEMTVGSPPQTLNILVDTGSSNFAVGAAPHPFLHRYYQRQLSST
YRDLRKGVYVPYTQGKWEGELGTDLVSIPHGPNVTVRANIAAITESDKFFINGSNWEGIL
GLAYAEIARPDDSLEPFFDSLVKQTHVPNLFSLQLCGAGFPLNQSEVLASVGGSMIIGGI
DHSLYTGSLWYTPIRREWYYEVIIVRVEINGQDLKMDCKEYNYDKSIVDSGTTNLRLPKK
VFEAAVKSIKAASSTEKFPDGFWLGEQLVCWQAGTTPWNIFPVISLYLMGEVTNQSFRIT
ILPQQYLRPVEDVATSQDDCYKFAISQSSTGTVMGAVIMEGFYVVFDRARKRIGFAVSAC
HVHDEFRTAAVEGPFVTLDMEDCGYNIPQTDESTLMTIAYVMAAICALFMLPLCLMVCQW
CCLRCLRQQHDDFADDISLLK
Number of residues
501
Molecular Weight
55710.28
Theoretical pI
5.19
GO Classification
Functions
aspartic-type endopeptidase activity / beta-amyloid binding / beta-aspartyl-peptidase activity / enzyme binding / peptidase activity
Processes
beta-amyloid metabolic process / cellular protein metabolic process / membrane protein ectodomain proteolysis / protein catabolic process / proteolysis
Components
axon / cell surface / cytoplasmic vesicle membrane / endoplasmic reticulum lumen / endosome / endosome membrane / Golgi apparatus / Golgi-associated vesicle lumen / integral component of membrane / integral component of plasma membrane / late endosome / multivesicular body / plasma membrane / trans-Golgi network
General Function
Peptidase activity
Specific Function
Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.
Pfam Domain Function
Transmembrane Regions
458-478
Cellular Location
Membrane
Gene sequence
>lcl|BSEQ0001966|1506 bp
ATGGCCCAAGCCCTGCCCTGGCTCCTGCTGTGGATGGGCGCGGGAGTGCTGCCTGCCCAC
GGCACCCAGCACGGCATCCGGCTGCCCCTGCGCAGCGGCCTGGGGGGCGCCCCCCTGGGG
CTGCGGCTGCCCCGGGAGACCGACGAAGAGCCCGAGGAGCCCGGCCGGAGGGGCAGCTTT
GTGGAGATGGTGGACAACCTGAGGGGCAAGTCGGGGCAGGGCTACTACGTGGAGATGACC
GTGGGCAGCCCCCCGCAGACGCTCAACATCCTGGTGGATACAGGCAGCAGTAACTTTGCA
GTGGGTGCTGCCCCCCACCCCTTCCTGCATCGCTACTACCAGAGGCAGCTGTCCAGCACA
TACCGGGACCTCCGGAAGGGTGTGTATGTGCCCTACACCCAGGGCAAGTGGGAAGGGGAG
CTGGGCACCGACCTGGTAAGCATCCCCCATGGCCCCAACGTCACTGTGCGTGCCAACATT
GCTGCCATCACTGAATCAGACAAGTTCTTCATCAACGGCTCCAACTGGGAAGGCATCCTG
GGGCTGGCCTATGCTGAGATTGCCAGGCCTGACGACTCCCTGGAGCCTTTCTTTGACTCT
CTGGTAAAGCAGACCCACGTTCCCAACCTCTTCTCCCTGCAGCTTTGTGGTGCTGGCTTC
CCCCTCAACCAGTCTGAAGTGCTGGCCTCTGTCGGAGGGAGCATGATCATTGGAGGTATC
GACCACTCGCTGTACACAGGCAGTCTCTGGTATACACCCATCCGGCGGGAGTGGTATTAT
GAGGTGATCATTGTGCGGGTGGAGATCAATGGACAGGATCTGAAAATGGACTGCAAGGAG
TACAACTATGACAAGAGCATTGTGGACAGTGGCACCACCAACCTTCGTTTGCCCAAGAAA
GTGTTTGAAGCTGCAGTCAAATCCATCAAGGCAGCCTCCTCCACGGAGAAGTTCCCTGAT
GGTTTCTGGCTAGGAGAGCAGCTGGTGTGCTGGCAAGCAGGCACCACCCCTTGGAACATT
TTCCCAGTCATCTCACTCTACCTAATGGGTGAGGTTACCAACCAGTCCTTCCGCATCACC
ATCCTTCCGCAGCAATACCTGCGGCCAGTGGAAGATGTGGCCACGTCCCAAGACGACTGT
TACAAGTTTGCCATCTCACAGTCATCCACGGGCACTGTTATGGGAGCTGTTATCATGGAG
GGCTTCTACGTTGTCTTTGATCGGGCCCGAAAACGAATTGGCTTTGCTGTCAGCGCTTGC
CATGTGCACGATGAGTTCAGGACGGCAGCGGTGGAAGGCCCTTTTGTCACCTTGGACATG
GAAGACTGTGGCTACAACATTCCACAGACAGATGAGTCAACCCTCATGACCATAGCCTAT
GTCATGGCTGCCATCTGCGCCCTCTTCATGCTGCCACTCTGCCTCATGGTGTGTCAGTGG
CGCTGCCTCCGCTGCCTGCGCCAGCAGCATGATGACTTTGCTGATGACATCTCCCTGCTG
AAGTGA
Chromosome Location
Not Available
Locus
11q23.2-q23.3
External Identifiers
ResourceLink
UniProtKB IDP56817
UniProtKB Entry NameBACE1_HUMAN
GenBank Protein ID6118539
GenBank Gene IDAF190725
GenAtlas IDBACE1
HGNC IDHGNC:933
General References
  1. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M: Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999 Oct 22;286(5440):735-41. [PubMed:10531052]
  2. Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P, Suomensaari SM, Wang S, Walker D, Zhao J, McConlogue L, John V: Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature. 1999 Dec 2;402(6761):537-40. [PubMed:10591214]
  3. Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME: Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature. 1999 Dec 2;402(6761):533-7. [PubMed:10591213]
  4. Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE, Southan CD, Ryan DM, Smith TS, Simmons DL, Walsh FS, Dingwall C, Christie G: Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci. 1999 Dec;14(6):419-27. [PubMed:10656250]
  5. Tanahashi H, Tabira T: Three novel alternatively spliced isoforms of the human beta-site amyloid precursor protein cleaving enzyme (BACE) and their effect on amyloid beta-peptide production. Neurosci Lett. 2001 Jul 6;307(1):9-12. [PubMed:11516562]
  6. Hirosawa M, Nagase T, Ishikawa K, Kikuno R, Nomura N, Ohara O: Characterization of cDNA clones selected by the GeneMark analysis from size-fractionated cDNA libraries from human brain. DNA Res. 1999 Oct 29;6(5):329-36. [PubMed:10574461]
  7. Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T: Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones. DNA Res. 2002 Jun 30;9(3):99-106. [PubMed:12168954]
  8. Taylor TD, Noguchi H, Totoki Y, Toyoda A, Kuroki Y, Dewar K, Lloyd C, Itoh T, Takeda T, Kim DW, She X, Barlow KF, Bloom T, Bruford E, Chang JL, Cuomo CA, Eichler E, FitzGerald MG, Jaffe DB, LaButti K, Nicol R, Park HS, Seaman C, Sougnez C, Yang X, Zimmer AR, Zody MC, Birren BW, Nusbaum C, Fujiyama A, Hattori M, Rogers J, Lander ES, Sakaki Y: Human chromosome 11 DNA sequence and analysis including novel gene identification. Nature. 2006 Mar 23;440(7083):497-500. [PubMed:16554811]
  9. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [PubMed:15489334]
  10. Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J: Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. [PubMed:10677483]
  11. Hussain I, Powell DJ, Howlett DR, Chapman GA, Gilmour L, Murdock PR, Tew DG, Meek TD, Chapman C, Schneider K, Ratcliffe SJ, Tattersall D, Testa TT, Southan C, Ryan DM, Simmons DL, Walsh FS, Dingwall C, Christie G: ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site. Mol Cell Neurosci. 2000 Nov;16(5):609-19. [PubMed:11083922]
  12. Yan R, Han P, Miao H, Greengard P, Xu H: The transmembrane domain of the Alzheimer's beta-secretase (BACE1) determines its late Golgi localization and access to beta -amyloid precursor protein (APP) substrate. J Biol Chem. 2001 Sep 28;276(39):36788-96. Epub 2001 Jul 20. [PubMed:11466313]
  13. Fischer F, Molinari M, Bodendorf U, Paganetti P: The disulphide bonds in the catalytic domain of BACE are critical but not essential for amyloid precursor protein processing activity. J Neurochem. 2002 Mar;80(6):1079-88. [PubMed:11953458]
  14. He X, Zhu G, Koelsch G, Rodgers KK, Zhang XC, Tang J: Biochemical and structural characterization of the interaction of memapsin 2 (beta-secretase) cytosolic domain with the VHS domain of GGA proteins. Biochemistry. 2003 Oct 28;42(42):12174-80. [PubMed:14567678]
  15. He W, Lu Y, Qahwash I, Hu XY, Chang A, Yan R: Reticulon family members modulate BACE1 activity and amyloid-beta peptide generation. Nat Med. 2004 Sep;10(9):959-65. Epub 2004 Aug 1. [PubMed:15286784]
  16. Murayama KS, Kametani F, Saito S, Kume H, Akiyama H, Araki W: Reticulons RTN3 and RTN4-B/C interact with BACE1 and inhibit its ability to produce amyloid beta-protein. Eur J Neurosci. 2006 Sep;24(5):1237-44. Epub 2006 Sep 8. [PubMed:16965550]
  17. He W, Hu X, Shi Q, Zhou X, Lu Y, Fisher C, Yan R: Mapping of interaction domains mediating binding between BACE1 and RTN/Nogo proteins. J Mol Biol. 2006 Oct 27;363(3):625-34. Epub 2006 Aug 11. [PubMed:16979658]
  18. Costantini C, Ko MH, Jonas MC, Puglielli L: A reversible form of lysine acetylation in the ER and Golgi lumen controls the molecular stabilization of BACE1. Biochem J. 2007 Nov 1;407(3):383-95. [PubMed:17425515]
  19. Jonas MC, Costantini C, Puglielli L: PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1. EMBO Rep. 2008 Sep;9(9):916-22. doi: 10.1038/embor.2008.132. Epub 2008 Jul 25. [PubMed:18660751]
  20. Ko MH, Puglielli L: Two endoplasmic reticulum (ER)/ER Golgi intermediate compartment-based lysine acetyltransferases post-translationally regulate BACE1 levels. J Biol Chem. 2009 Jan 23;284(4):2482-92. doi: 10.1074/jbc.M804901200. Epub 2008 Nov 14. [PubMed:19011241]
  21. Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW: Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Aug;24(8):2783-94. doi: 10.1096/fj.09-146357. Epub 2010 Mar 30. [PubMed:20354142]
  22. Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK, Zhang XC, Tang J: Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science. 2000 Oct 6;290(5489):150-3. [PubMed:11021803]
  23. Hong L, Turner RT 3rd, Koelsch G, Shin D, Ghosh AK, Tang J: Crystal structure of memapsin 2 (beta-secretase) in complex with an inhibitor OM00-3. Biochemistry. 2002 Sep 10;41(36):10963-7. [PubMed:12206667]
  24. Hong L, Tang J: Flap position of free memapsin 2 (beta-secretase), a model for flap opening in aspartic protease catalysis. Biochemistry. 2004 Apr 27;43(16):4689-95. [PubMed:15096037]
  25. Patel S, Vuillard L, Cleasby A, Murray CW, Yon J: Apo and inhibitor complex structures of BACE (beta-secretase). J Mol Biol. 2004 Oct 15;343(2):407-16. [PubMed:15451669]
  26. Turner RT 3rd, Hong L, Koelsch G, Ghosh AK, Tang J: Structural locations and functional roles of new subsites S5, S6, and S7 in memapsin 2 (beta-secretase). Biochemistry. 2005 Jan 11;44(1):105-12. [PubMed:15628850]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB02378MMI-175experimentalunknownDetails
DB06073CTS-21166investigationalyesinhibitorDetails
DB06930N-[amino(imino)methyl]-2-(2,5-diphenyl-1H-pyrrol-1-yl)acetamideexperimentalunknownDetails
DB07019N-[(5R,14R)-5-AMINO-5,14-DIMETHYL-4-OXO-3-OXA-18-AZATRICYCLO[15.3.1.1~7,11~]DOCOSA-1(21),7(22),8,10,17,19-HEXAEN-19-YL]-N-METHYLMETHANESULFONAMIDEexperimentalunknownDetails
DB07089N-[amino(imino)methyl]-2-[2-(2-chlorophenyl)-4-(4-propoxyphenyl)-3-thienyl]acetamideexperimentalunknownDetails
DB071104-(4-FLUOROBENZYL)PIPERIDINEexperimentalunknownDetails
DB07175N-{2-methyl-5-[(6-phenylpyrimidin-4-yl)amino]phenyl}methanesulfonamideexperimentalunknownDetails
DB072066-[2-(1H-INDOL-6-YL)ETHYL]PYRIDIN-2-AMINEexperimentalunknownDetails
DB072456-[2-(3'-METHOXYBIPHENYL-3-YL)ETHYL]PYRIDIN-2-AMINEexperimentalunknownDetails
DB07281N~3~-BENZYLPYRIDINE-2,3-DIAMINEexperimentalunknownDetails
DB07284N~3~-(3-PYRIDIN-3-YLBENZYL)PYRIDINE-2,3-DIAMINEexperimentalunknownDetails
DB07303N~3~-[3-(5-METHOXYPYRIDIN-3-YL)BENZYL]PYRIDINE-2,3-DIAMINEexperimentalunknownDetails
DB073454-(2-aminoethyl)-2-cyclohexylphenolexperimentalunknownDetails
DB073464-(2-aminoethyl)-2-ethylphenolexperimentalunknownDetails
DB074154-[(1S)-1-(3-fluoro-4-methoxyphenyl)-2-(2-methoxy-5-nitrophenyl)ethyl]-1H-imidazol-2-amineexperimentalunknownDetails
DB07519(6R)-2-amino-6-[2-(3'-methoxybiphenyl-3-yl)ethyl]-3,6-dimethyl-5,6-dihydropyrimidin-4(3H)-oneexperimentalunknownDetails
DB075352-amino-6-[2-(1H-indol-6-yl)ethyl]pyrimidin-4(3H)-oneexperimentalunknownDetails
DB07573(2S)-1-(2,5-dimethylphenoxy)-3-morpholin-4-ylpropan-2-olexperimentalunknownDetails
DB07734N-(1-benzylpiperidin-4-yl)-4-sulfanylbutanamideexperimentalunknownDetails
DB07735N-[1-(2,6-dimethoxybenzyl)piperidin-4-yl]-4-sulfanylbutanamideexperimentalunknownDetails
DB07736(2S)-4-(4-fluorobenzyl)-N-(2-sulfanylethyl)piperazine-2-carboxamideexperimentalunknownDetails
DB07737(2S)-4-(4-fluorobenzyl)-N-(3-sulfanylpropyl)piperazine-2-carboxamideexperimentalunknownDetails
DB07738N-[1-(5-bromo-2,3-dimethoxybenzyl)piperidin-4-yl]-4-sulfanylbutanamideexperimentalunknownDetails
DB07874(6S)-2-amino-6-(3'-methoxybiphenyl-3-yl)-3,6-dimethyl-5,6-dihydropyrimidin-4(3H)-oneexperimentalunknownDetails
DB07993N~3~-[3-(1H-INDOL-6-YL)BENZYL]PYRIDINE-2,3-DIAMINEexperimentalunknownDetails
DB07994N~3~-[5-(1H-INDOL-6-YL)-2-(PYRIDIN-2-YLMETHOXY)BENZYL]PYRIDINE-2,3-DIAMINEexperimentalunknownDetails
DB087493-(2-AMINO-6-BENZOYLQUINAZOLIN-3(4H)-YL)-N-CYCLOHEXYL-N-METHYLPROPANAMIDEexperimentalunknownDetails
DB12285VerubecestatinvestigationalyesinhibitorDetails