Beta-secretase 2

Beta-secretase 2 ({{EC number|3.4.23.45}}, also known as Memapsin-1) is an enzyme{{cite journal | vauthors = Turner RT, Loy JA, Nguyen C, Devasamudram T, Ghosh AK, Koelsch G, Tang J | title = Specificity of memapsin 1 and its implications on the design of memapsin 2 (beta-secretase) inhibitor selectivity | journal = Biochemistry | volume = 41 | issue = 27 | pages = 8742–8746 | date = July 2002 | pmid = 12093293 | doi = 10.1021/bi025926t }}{{cite journal | vauthors = Solans A, Estivill X, de La Luna S | title = A new aspartyl protease on 21q22.3, BACE2, is highly similar to Alzheimer's amyloid precursor protein beta-secretase | journal = Cytogenetics and Cell Genetics | volume = 89 | issue = 3–4 | pages = 177–184 | date = Sep 2000 | pmid = 10965118 | doi = 10.1159/000015608 | s2cid = 39880508 }}{{cite journal | vauthors = 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 | title = The DNA sequence of human chromosome 21 | journal = Nature | volume = 405 | issue = 6784 | pages = 311–319 | date = May 2000 | pmid = 10830953 | doi = 10.1038/35012518 | bibcode = 2000Natur.405..311H | doi-access = free }}{{cite web | title = Entrez Gene: BACE2 beta-site APP-cleaving enzyme 2 | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=25825 }} 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.

Gene

This gene is located in the "Down critical region" of chromosome 21, which has been implicated in the pathogenesis of Down syndrome. Three transcript variants encoding different isoforms have been described for this gene.

Function

The protein encoded by this gene is a member of the peptidase A1 family, and functions as a type I integral membrane glycoprotein and aspartic protease. It is involved in the proteolytic cleavage of amyloid precursor protein (APP), a key step in the production of amyloid beta peptide. Cerebral deposition of amyloid beta peptide is an early and critical feature of Alzheimer's disease and a common complication in Down syndrome.

BACE2 has also been identified as the primary protease responsible for the release of the amyloidogenic ectodomain of Pmel17 in melanocytes, a process essential for the formation of the melanosome amyloid matrix.{{cite journal | vauthors = Rochin L, Hurbain I, Serneels L, Fort C, Watt B, Leblanc P, Marks MS, De Strooper B, Raposo G, Van Niel G | title = BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 26 | pages = 10658–10663 | date = Jun 2013 | pmid = 23754390 | pmc = 3696817 | doi = 10.1073/pnas.1220748110 | bibcode = 2013PNAS..11010658R | doi-access = free }}

Clinical significance

BACE2 has been implicated in the maintenance of pancreatic β cells and regulation of glucose homeostasis. In mouse models, higher BACE2 activity has been associated with improved pancreatic function, suggesting potential therapeutic relevance for Type 2 Diabetes research.{{Cite journal | vauthors = Esterházy D, Stützer I, Wang H, Rechsteiner MP, Beauchamp J, Döbeli H, Hilpert H, Matile H, Prummer M, Schmidt A, Lieske N | title = Bace2 is a β cell-enriched protease that regulates pancreatic β cell function and mass | journal = Cell Metabolism | volume = 14 | issue = 3 | pages = 365–377 | date = 2011-09-07 | pmid = 21907142 | doi = 10.1016/j.cmet.2011.06.018 | issn = 1932-7420 | doi-access = free }}

In a separate context, a homozygous 25-base pair deletion in the BACE2 gene has been linked to the unique brown-and-white coat coloration in some giant pandas, as opposed to the typical black-and-white phenotype observed in the wild type.*{{cite journal | vauthors = Guan D, Sun S, Song L, Zhao P, Nie Y, Huang X, Zhou W, Yan L, Lei Y, Hu Y, Wei F | title = Taking a color photo: A homozygous 25-bp deletion in Bace2 may cause brown-and-white coat color in giant pandas | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 121 | issue = 11 | pages = e2317430121 | date = Mar 2024 | pmid = 38437540 | pmc = 10945837 | doi = 10.1073/pnas.2317430121 | doi-access = free }}

Interactions

BACE2 has been shown to interact with GGA1{{cite journal | vauthors = He X, Chang WP, Koelsch G, Tang J | title = Memapsin 2 (beta-secretase) cytosolic domain binds to the VHS domains of GGA1 and GGA2: implications on the endocytosis mechanism of memapsin 2 | journal = FEBS Letters | volume = 524 | issue = 1–3 | pages = 183–187 | date = Jul 2002 | pmid = 12135764 | doi = 10.1016/S0014-5793(02)03052-1 | s2cid = 42042430 | doi-access = free }} and GGA2.

References

{{cite journal | vauthors = Aplin AE, Gibb GM, Jacobsen JS, Gallo JM, Anderton BH | title = In vitro phosphorylation of the cytoplasmic domain of the amyloid precursor protein by glycogen synthase kinase-3beta | journal = Journal of Neurochemistry | volume = 67 | issue = 2 | pages = 699–707 | date = Aug 1996 | pmid = 8764598 | doi = 10.1046/j.1471-4159.1996.67020699.x | s2cid = 11133791 }}
{{cite journal | vauthors = 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 | title = Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity | journal = Nature | volume = 402 | issue = 6761 | pages = 533–537 | date = Dec 1999 | pmid = 10591213 | doi = 10.1038/990107 | bibcode = 1999Natur.402..533Y | s2cid = 4320087 }}
{{cite journal | vauthors = Sadik G, Kaji H, Takeda K, Yamagata F, Kameoka Y, Hashimoto K, Miyanaga K, Shinoda T | title = In vitro processing of amyloid precursor protein by cathepsin D | journal = The International Journal of Biochemistry & Cell Biology | volume = 31 | issue = 11 | pages = 1327–1337 | date = Nov 1999 | pmid = 10605825 | doi = 10.1016/S1357-2725(99)00053-9 }}
{{cite journal | vauthors = 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 | title = Identification of a novel aspartic protease (Asp 2) as beta-secretase | journal = Molecular and Cellular Neurosciences | volume = 14 | issue = 6 | pages = 419–427 | date = Dec 1999 | pmid = 10656250 | doi = 10.1006/mcne.1999.0811 | s2cid = 54308213 }}
{{cite journal | vauthors = Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J | title = Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 4 | pages = 1456–1460 | date = Feb 2000 | pmid = 10677483 | pmc = 26455 | doi = 10.1073/pnas.97.4.1456 | bibcode = 2000PNAS...97.1456L | doi-access = free }}
{{cite journal | vauthors = Acquati F, Accarino M, Nucci C, Fumagalli P, Jovine L, Ottolenghi S, Taramelli R | title = The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of the aspartic protease family, maps to the down critical region | journal = FEBS Letters | volume = 468 | issue = 1 | pages = 59–64 | date = Feb 2000 | pmid = 10683441 | doi = 10.1016/S0014-5793(00)01192-3 | s2cid = 30941017 }}
{{cite journal | vauthors = Bennett BD, Babu-Khan S, Loeloff R, Louis JC, Curran E, Citron M, Vassar R | title = Expression analysis of BACE2 in brain and peripheral tissues | journal = The Journal of Biological Chemistry | volume = 275 | issue = 27 | pages = 20647–20651 | date = Jul 2000 | pmid = 10749877 | doi = 10.1074/jbc.M002688200 | doi-access = free }}
{{cite journal | vauthors = Xin H, Stephans JC, Duan X, Harrowe G, Kim E, Grieshammer U, Kingsley C, Giese K | title = Identification of a novel aspartic-like protease differentially expressed in human breast cancer cell lines | journal = Biochimica et Biophysica Acta | volume = 1501 | issue = 2–3 | pages = 125–137 | date = Jun 2000 | pmid = 10838186 | doi = 10.1016/s0925-4439(00)00014-4 }}
{{cite journal | vauthors = Farzan M, Schnitzler CE, Vasilieva N, Leung D, Choe H | title = BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 17 | pages = 9712–9717 | date = Aug 2000 | pmid = 10931940 | pmc = 16930 | doi = 10.1073/pnas.160115697 | bibcode = 2000PNAS...97.9712F | doi-access = free }}
{{cite journal | vauthors = Iijima K, Ando K, Takeda S, Satoh Y, Seki T, Itohara S, Greengard P, Kirino Y, Nairn AC, Suzuki T | title = Neuron-specific phosphorylation of Alzheimer's beta-amyloid precursor protein by cyclin-dependent kinase 5 | journal = Journal of Neurochemistry | volume = 75 | issue = 3 | pages = 1085–1091 | date = Sep 2000 | pmid = 10936190 | doi = 10.1046/j.1471-4159.2000.0751085.x | s2cid = 41050912 }}
{{cite journal | vauthors = 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 | title = ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site | journal = Molecular and Cellular Neurosciences | volume = 16 | issue = 5 | pages = 609–619 | date = Nov 2000 | pmid = 11083922 | doi = 10.1006/mcne.2000.0884 | s2cid = 54379424 }}
{{cite journal | vauthors = Hussain I, Christie G, Schneider K, Moore S, Dingwall C | title = Prodomain processing of Asp1 (BACE2) is autocatalytic | journal = The Journal of Biological Chemistry | volume = 276 | issue = 26 | pages = 23322–23328 | date = Jun 2001 | pmid = 11316808 | doi = 10.1074/jbc.M101069200 | doi-access = free }}
{{cite journal | vauthors = Yan R, Munzner JB, Shuck ME, Bienkowski MJ | title = BACE2 functions as an alternative alpha-secretase in cells | journal = The Journal of Biological Chemistry | volume = 276 | issue = 36 | pages = 34019–34027 | date = Sep 2001 | pmid = 11423558 | doi = 10.1074/jbc.M105583200 | doi-access = free }}
{{cite journal | vauthors = Grüninger-Leitch F, Schlatter D, Küng E, Nelböck P, Döbeli H | title = Substrate and inhibitor profile of BACE (beta-secretase) and comparison with other mammalian aspartic proteases | journal = The Journal of Biological Chemistry | volume = 277 | issue = 7 | pages = 4687–4693 | date = Feb 2002 | pmid = 11741910 | doi = 10.1074/jbc.M109266200 | doi-access = free }}
{{cite journal | vauthors = Kim YT, Downs D, Wu S, Dashti A, Pan Y, Zhai P, Wang X, Zhang XC, Lin X | title = Enzymic properties of recombinant BACE2 | journal = European Journal of Biochemistry | volume = 269 | issue = 22 | pages = 5668–5677 | date = Nov 2002 | pmid = 12423367 | doi = 10.1046/j.1432-1033.2002.03277.x | doi-access = free }}
{{cite journal | vauthors = Kondoh K, Tsuji N, Kamagata C, Sasaki M, Kobayashi D, Yagihashi A, Watanabe N | title = A novel aspartic protease gene, ALP56, is up-regulated in human breast cancer independently from the cathepsin D gene | journal = Breast Cancer Research and Treatment | volume = 78 | issue = 1 | pages = 37–44 | date = Mar 2003 | pmid = 12611455 | doi = 10.1023/A:1022149226430 | s2cid = 2195115 }}

External links

https://web.archive.org/web/20070318110931/http://www.ihop-net.org/UniPub/iHOP/gs/129262.html
{{OMIM|605668}}
{{UCSC gene info|BACE2}}

Category:EC 3.4.23