Beta-secretase 2
Beta-secretase 2 is an enzyme that in humans is encoded by the BACE2 gene.[1][2][3]
BACE2 is a close homolog of BACE1, a protease known to be an important enzyme involved in the cellular pathways that some believe lead to Alzheimer's disease. The physiological function and role of BACE2 in Alzheimer's disease is unknown.
Function
Cerebral deposition of amyloid beta peptide is an early and critical feature of Alzheimer's disease and a frequent complication of Down syndrome. Amyloid beta peptide is generated by proteolytic cleavage of amyloid precursor protein by 2 proteases, one of which is the protein encoded by this gene. This gene localizes to the 'Down critical region' of chromosome 21. The encoded protein, a member of the peptidase A1 protein family, is a type I integral membrane glycoprotein and aspartic protease. Three transcript variants encoding different isoforms have been described for this gene.[3]
Interactions
BACE2 has been shown to interact with GGA1[4] and GGA2.[4]
References
- ^ Solans A, Estivill X, de La Luna S (Sep 2000). "A new aspartyl protease on 21q22.3, BACE2, is highly similar to Alzheimer's amyloid precursor protein beta-secretase". Cytogenet Cell Genet 89 (3-4): 177–84. doi:10.1159/000015608. PMID 10965118.
- ^ Hattori M, Fujiyama A, Taylor TD, Watanabe H, Yada T, Park HS, Toyoda A, Ishii K, Totoki Y, Choi DK, Groner Y, Soeda E, Ohki M, Takagi T, Sakaki Y, Taudien S, Blechschmidt K, Polley A, Menzel U, Delabar J, Kumpf K, Lehmann R, Patterson D, Reichwald K, Rump A, Schillhabel M, Schudy A, Zimmermann W, Rosenthal A, Kudoh J, Schibuya K, Kawasaki K, Asakawa S, Shintani A, Sasaki T, Nagamine K, Mitsuyama S, Antonarakis SE, Minoshima S, Shimizu N, Nordsiek G, Hornischer K, Brant P, Scharfe M, Schon O, Desario A, Reichelt J, Kauer G, Blocker H, Ramser J, Beck A, Klages S, Hennig S, Riesselmann L, Dagand E, Haaf T, Wehrmeyer S, Borzym K, Gardiner K, Nizetic D, Francis F, Lehrach H, Reinhardt R, Yaspo ML (Jun 2000). "The DNA sequence of human chromosome 21". Nature 405 (6784): 311–9. doi:10.1038/35012518. PMID 10830953.
- ^ a b "Entrez Gene: BACE2 beta-site APP-cleaving enzyme 2". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=25825.
- ^ a b He, Xiangyuan; Chang Wan-Pin, Koelsch Gerald, Tang Jordan (Jul. 2002). "Memapsin 2 (beta-secretase) cytosolic domain binds to the VHS domains of GGA1 and GGA2: implications on the endocytosis mechanism of memapsin 2". FEBS Lett. (Netherlands) 524 (1-3): 183–7. doi:10.1016/S0014-5793(02)03052-1. ISSN 0014-5793. PMID 12135764.
Further reading
- Aplin AE, Gibb GM, Jacobsen JS, et al. (1996). "In vitro phosphorylation of the cytoplasmic domain of the amyloid precursor protein by glycogen synthase kinase-3beta". J. Neurochem. 67 (2): 699–707. doi:10.1046/j.1471-4159.1996.67020699.x. PMID 8764598.
- Yan R, Bienkowski MJ, Shuck ME, et al. (1999). "Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity". Nature 402 (6761): 533–7. doi:10.1038/990107. PMID 10591213.
- Sadik G, Kaji H, Takeda K, et al. (2000). "In vitro processing of amyloid precursor protein by cathepsin D". Int. J. Biochem. Cell Biol. 31 (11): 1327–37. doi:10.1016/S1357-2725(99)00053-9. PMID 10605825.
- Hussain I, Powell D, Howlett DR, et al. (2000). "Identification of a novel aspartic protease (Asp 2) as beta-secretase". Mol. Cell. Neurosci. 14 (6): 419–27. doi:10.1006/mcne.1999.0811. PMID 10656250.
- Lin X, Koelsch G, Wu S, et al. (2000). "Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein". Proc. Natl. Acad. Sci. U.S.A. 97 (4): 1456–60. doi:10.1073/pnas.97.4.1456. PMC 26455. PMID 10677483. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=26455.
- Acquati F, Accarino M, Nucci C, et al. (2000). "The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of the aspartic protease family, maps to the down critical region". FEBS Lett. 468 (1): 59–64. doi:10.1016/S0014-5793(00)01192-3. PMID 10683441.
- Bennett BD, Babu-Khan S, Loeloff R, et al. (2000). "Expression analysis of BACE2 in brain and peripheral tissues". J. Biol. Chem. 275 (27): 20647–51. doi:10.1074/jbc.M002688200. PMID 10749877.
- Xin H, Stephans JC, Duan X, et al. (2000). "Identification of a novel aspartic-like protease differentially expressed in human breast cancer cell lines". Biochim. Biophys. Acta 1501 (2-3): 125–37. PMID 10838186.
- Farzan M, Schnitzler CE, Vasilieva N, et al. (2000). "BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein". Proc. Natl. Acad. Sci. U.S.A. 97 (17): 9712–7. doi:10.1073/pnas.160115697. PMC 16930. PMID 10931940. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=16930.
- Iijima K, Ando K, Takeda S, et al. (2000). "Neuron-specific phosphorylation of Alzheimer's beta-amyloid precursor protein by cyclin-dependent kinase 5". J. Neurochem. 75 (3): 1085–91. doi:10.1046/j.1471-4159.2000.0751085.x. PMID 10936190.
- Hussain I, Powell DJ, Howlett DR, et al. (2001). "ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site". Mol. Cell. Neurosci. 16 (5): 609–19. doi:10.1006/mcne.2000.0884. PMID 11083922.
- Hussain I, Christie G, Schneider K, et al. (2001). "Prodomain processing of Asp1 (BACE2) is autocatalytic". J. Biol. Chem. 276 (26): 23322–8. doi:10.1074/jbc.M101069200. PMID 11316808.
- Yan R, Munzner JB, Shuck ME, Bienkowski MJ (2001). "BACE2 functions as an alternative alpha-secretase in cells". J. Biol. Chem. 276 (36): 34019–27. doi:10.1074/jbc.M105583200. PMID 11423558.
- Grüninger-Leitch F, Schlatter D, Küng E, et al. (2002). "Substrate and inhibitor profile of BACE (beta-secretase) and comparison with other mammalian aspartic proteases". J. Biol. Chem. 277 (7): 4687–93. doi:10.1074/jbc.M109266200. PMID 11741910.
- Turner RT, Loy JA, Nguyen C, et al. (2002). "Specificity of memapsin 1 and its implications on the design of memapsin 2 (beta-secretase) inhibitor selectivity". Biochemistry 41 (27): 8742–6. doi:10.1021/bi025926t. PMID 12093293.
- Kim YT, Downs D, Wu S, et al. (2003). "Enzymic properties of recombinant BACE2". Eur. J. Biochem. 269 (22): 5668–77. doi:10.1046/j.1432-1033.2002.03277.x. PMID 12423367.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241.
- Kondoh K, Tsuji N, Kamagata C, et al. (2003). "A novel aspartic protease gene, ALP56, is up-regulated in human breast cancer independently from the cathepsin D gene". Breast Cancer Res. Treat. 78 (1): 37–44. doi:10.1023/A:1022149226430. PMID 12611455.
External links
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PDB gallery
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2ewy: Crystal structure of human BACE2 in complex with a hydroxyethylenamine transition-state inhibitor
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