Beta-secretase 2

Beta-secretase 2 (EC 3.4.23.45, also known as Memapsin-1) is an enzyme[5][6][7][8] that cleaves Glu-Val-Asn-Leu!Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid precursor protein. BACE2 is a close homolog of BACE1.

BACE2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2EWY, 3ZKG, 3ZKI, 3ZKM, 3ZKN, 3ZKQ, 3ZKS, 3ZKX, 3ZL7, 3ZLQ, 4BEL, 4BFB
Identifiers
Aliases	BACE2, AEPLC, ALP56, ASP1, ASP21, BAE2, CDA13, CEAP1, DRAP, beta-site APP-cleaving enzyme 2, beta-secretase 2
External IDs	OMIM: 605668 MGI: 1860440 HomoloGene: 22696 GeneCards: BACE2
Gene location (Human) Chr. Chromosome 21 (human)[1] Band 21q22.2-q22.3 Start 41,167,801 bp[1] End 41,282,530 bp[1]
Gene location (Mouse) Chr. Chromosome 16 (mouse)[2] Band 16|16 C4 Start 97,356,742 bp[2] End 97,442,936 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • peptidase activity • amyloid-beta binding • hydrolase activity • aspartic-type endopeptidase activity Cellular component • integral component of membrane • cell surface • endosome • Golgi apparatus • endoplasmic reticulum • membrane • cell membrane • cytoplasm • trans-Golgi network • dense core granule Biological process • peptide hormone processing • protein catabolic process • amyloid-beta metabolic process • negative regulation of amyloid precursor protein biosynthetic process • proteolysis • membrane protein ectodomain proteolysis • astrocyte activation • glucose homeostasis Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	25825	56175
Ensembl	ENSG00000182240	ENSMUSG00000040605
UniProt	Q9Y5Z0	Q9JL18
RefSeq (mRNA)	NM_138992 NM_012105 NM_138991	NM_019517
RefSeq (protein)	NP_036237 NP_620476 NP_620477	NP_062390
Location (UCSC)	Chr 21: 41.17 – 41.28 Mb	Chr 16: 97.36 – 97.44 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[8] It has been reported that BACE2 is the main protease that mediates the release of the amyloidogenic ectodomain of Pmel17 in melanocytes. [9]

Interactions

BACE2 has been shown to interact with GGA1[10] and GGA2.[10]

References

1. GRCh38: Ensembl release 89: ENSG00000182240 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000040605 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Turner, R.T.; Loy, J.A.; Nguyen, C.; Devasamudram, T.; Ghosh, A.K.; Koelsch, G.; Tang, J. (2002). "Specificity of memapsin 1 and its implications on the design of memapsin 2 (β-secretase) inhibitor selectivity". Biochemistry. 41 (27): 8742–8746. doi:10.1021/bi025926t. PMID 12093293.
6. 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". Cytogenetics and Cell Genetics. 89 (3–4): 177–84. doi:10.1159/000015608. PMID 10965118.
7. 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 (May 2000). "The DNA sequence of human chromosome 21". Nature. 405 (6784): 311–9. Bibcode:2000Natur.405..311H. doi:10.1038/35012518. PMID 10830953.
8. "Entrez Gene: BACE2 beta-site APP-cleaving enzyme 2".
9. BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells Pubmed
10. He X, Chang WP, Koelsch G, Tang J (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 Letters. 524 (1–3): 183–7. doi:10.1016/S0014-5793(02)03052-1. PMID 12135764.

Further reading

• Aplin AE, Gibb GM, Jacobsen JS, Gallo JM, Anderton BH (Aug 1996). "In vitro phosphorylation of the cytoplasmic domain of the amyloid precursor protein by glycogen synthase kinase-3beta". Journal of Neurochemistry. 67 (2): 699–707. doi:10.1046/j.1471-4159.1996.67020699.x. PMID 8764598.
• 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 (Dec 1999). "Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity". Nature. 402 (6761): 533–7. Bibcode:1999Natur.402..533Y. doi:10.1038/990107. PMID 10591213.
• Sadik G, Kaji H, Takeda K, Yamagata F, Kameoka Y, Hashimoto K, Miyanaga K, Shinoda T (Nov 1999). "In vitro processing of amyloid precursor protein by cathepsin D". The International Journal of Biochemistry & Cell Biology. 31 (11): 1327–37. doi:10.1016/S1357-2725(99)00053-9. PMID 10605825.
• 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 (Dec 1999). "Identification of a novel aspartic protease (Asp 2) as beta-secretase". Molecular and Cellular Neurosciences. 14 (6): 419–27. doi:10.1006/mcne.1999.0811. PMID 10656250.
• Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J (Feb 2000). "Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein". Proceedings of the National Academy of Sciences of the United States of America. 97 (4): 1456–60. doi:10.1073/pnas.97.4.1456. PMC 26455. PMID 10677483.
• Acquati F, Accarino M, Nucci C, Fumagalli P, Jovine L, Ottolenghi S, Taramelli R (Feb 2000). "The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of the aspartic protease family, maps to the down critical region". FEBS Letters. 468 (1): 59–64. doi:10.1016/S0014-5793(00)01192-3. PMID 10683441.
• Bennett BD, Babu-Khan S, Loeloff R, Louis JC, Curran E, Citron M, Vassar R (Jul 2000). "Expression analysis of BACE2 in brain and peripheral tissues". The Journal of Biological Chemistry. 275 (27): 20647–51. doi:10.1074/jbc.M002688200. PMID 10749877.
• Xin H, Stephans JC, Duan X, Harrowe G, Kim E, Grieshammer U, Kingsley C, Giese K (Jun 2000). "Identification of a novel aspartic-like protease differentially expressed in human breast cancer cell lines". Biochimica et Biophysica Acta. 1501 (2–3): 125–37. doi:10.1016/s0925-4439(00)00014-4. PMID 10838186.
• Farzan M, Schnitzler CE, Vasilieva N, Leung D, Choe H (Aug 2000). "BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein". Proceedings of the National Academy of Sciences of the United States of America. 97 (17): 9712–7. doi:10.1073/pnas.160115697. PMC 16930. PMID 10931940.
• Iijima K, Ando K, Takeda S, Satoh Y, Seki T, Itohara S, Greengard P, Kirino Y, Nairn AC, Suzuki T (Sep 2000). "Neuron-specific phosphorylation of Alzheimer's beta-amyloid precursor protein by cyclin-dependent kinase 5". Journal of Neurochemistry. 75 (3): 1085–91. doi:10.1046/j.1471-4159.2000.0751085.x. PMID 10936190.
• 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 (Nov 2000). "ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site". Molecular and Cellular Neurosciences. 16 (5): 609–19. doi:10.1006/mcne.2000.0884. PMID 11083922.
• Hussain I, Christie G, Schneider K, Moore S, Dingwall C (Jun 2001). "Prodomain processing of Asp1 (BACE2) is autocatalytic". The Journal of Biological Chemistry. 276 (26): 23322–8. doi:10.1074/jbc.M101069200. PMID 11316808.
• Yan R, Munzner JB, Shuck ME, Bienkowski MJ (Sep 2001). "BACE2 functions as an alternative alpha-secretase in cells". The Journal of Biological Chemistry. 276 (36): 34019–27. doi:10.1074/jbc.M105583200. PMID 11423558.
• Grüninger-Leitch F, Schlatter D, Küng E, Nelböck P, Döbeli H (Feb 2002). "Substrate and inhibitor profile of BACE (beta-secretase) and comparison with other mammalian aspartic proteases". The Journal of Biological Chemistry. 277 (7): 4687–93. doi:10.1074/jbc.M109266200. PMID 11741910.
• Turner RT, Loy JA, Nguyen C, Devasamudram T, Ghosh AK, Koelsch G, Tang J (Jul 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, Dashti A, Pan Y, Zhai P, Wang X, Zhang XC, Lin X (Nov 2002). "Enzymic properties of recombinant BACE2". European Journal of Biochemistry / FEBS. 269 (22): 5668–77. doi:10.1046/j.1432-1033.2002.03277.x. PMID 12423367.
• Kondoh K, Tsuji N, Kamagata C, Sasaki M, Kobayashi D, Yagihashi A, Watanabe N (Mar 2003). "A novel aspartic protease gene, ALP56, is up-regulated in human breast cancer independently from the cathepsin D gene". Breast Cancer Research and Treatment. 78 (1): 37–44. doi:10.1023/A:1022149226430. PMID 12611455.

External links

• https://web.archive.org/web/20070318110931/http://www.ihop-net.org/UniPub/iHOP/gs/129262.html
• Online Mendelian Inheritance in Man (OMIM): 605668
• Human BACE2 genome location and BACE2 gene details page in the UCSC Genome Browser.