Beta-secretase 2

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; OMA:BACE2 - orthologs
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 97,157,942 bp [2] End 97,244,136 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in parotid gland gallbladder pancreatic ductal cell minor salivary glands renal medulla islet of Langerhans pylorus ascending aorta Descending thoracic aorta saphenous vein Top expressed in pyloric antrum epithelium of stomach transitional epithelium of urinary bladder islet of Langerhans iris mucous cell of stomach sciatic nerve conjunctival fornix aortic valve stria vascularis More reference expression data BioGPS 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 plasma 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: 97.16 – 97.24 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.

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. ^[8]

Function

See also: integral membrane protein and glycoprotein

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. ^[9]

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. ^[10] 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. ^[11]

Interactions

BACE2 has been shown to interact with GGA1 ^[12] and GGA2. ^[12]

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 RT, Loy JA, Nguyen C, Devasamudram T, Ghosh AK, Koelsch G, et al. (July 2002). "Specificity of memapsin 1 and its implications on the design of memapsin 2 (beta-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): 177–184. doi:10.1159/000015608. PMID   10965118. S2CID   39880508.
7. Hattori M, Fujiyama A, Taylor TD, Watanabe H, Yada T, Park HS, et al. (May 2000). "The DNA sequence of human chromosome 21". Nature. 405 (6784): 311–319. Bibcode:2000Natur.405..311H. doi: 10.1038/35012518 . PMID   10830953.
8. "Entrez Gene: BACE2 beta-site APP-cleaving enzyme 2".
9. Rochin L, Hurbain I, Serneels L, Fort C, Watt B, Leblanc P, et al. (Jun 2013). "BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells". Proceedings of the National Academy of Sciences of the United States of America. 110 (26): 10658–10663. Bibcode:2013PNAS..11010658R. doi: 10.1073/pnas.1220748110 . PMC   3696817 . PMID   23754390.
10. Esterházy D, Stützer I, Wang H, Rechsteiner MP, Beauchamp J, Döbeli H, et al. (2011-09-07). "Bace2 is a β cell-enriched protease that regulates pancreatic β cell function and mass". Cell Metabolism. 14 (3): 365–377. doi: 10.1016/j.cmet.2011.06.018 . ISSN   1932-7420. PMID   21907142.
11. • Guan D, Sun S, Song L, Zhao P, Nie Y, Huang X, et al. (Mar 2024). "Taking a color photo: A homozygous 25-bp deletion in Bace2 may cause brown-and-white coat color in giant pandas". Proceedings of the National Academy of Sciences of the United States of America. 121 (11): e2317430121. Bibcode:2024PNAS..12117430G. doi: 10.1073/pnas.2317430121 . PMC   10945837 . PMID   38437540.
12. 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): 183–187. Bibcode:2002FEBSL.524..183H. doi: 10.1016/S0014-5793(02)03052-1 . PMID   12135764. S2CID   42042430.

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. S2CID   11133791.
• Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, et al. (Dec 1999). "Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity". Nature. 402 (6761): 533–537. Bibcode:1999Natur.402..533Y. doi:10.1038/990107. PMID   10591213. S2CID   4320087.
• Sadik G, Kaji H, Takeda K, Yamagata F, Kameoka Y, Hashimoto K, et al. (Nov 1999). "In vitro processing of amyloid precursor protein by cathepsin D". The International Journal of Biochemistry & Cell Biology. 31 (11): 1327–1337. doi:10.1016/S1357-2725(99)00053-9. PMID   10605825.
• Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, et al. (Dec 1999). "Identification of a novel aspartic protease (Asp 2) as beta-secretase". Molecular and Cellular Neurosciences. 14 (6): 419–427. doi:10.1006/mcne.1999.0811. PMID   10656250. S2CID   54308213.
• 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): 1456–1460. Bibcode:2000PNAS...97.1456L. doi: 10.1073/pnas.97.4.1456 . PMC   26455 . PMID   10677483.
• Acquati F, Accarino M, Nucci C, Fumagalli P, Jovine L, Ottolenghi S, et al. (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. Bibcode:2000FEBSL.468...59A. doi:10.1016/S0014-5793(00)01192-3. PMID   10683441. S2CID   30941017.
• Bennett BD, Babu-Khan S, Loeloff R, Louis JC, Curran E, Citron M, et al. (Jul 2000). "Expression analysis of BACE2 in brain and peripheral tissues". The Journal of Biological Chemistry. 275 (27): 20647–20651. doi: 10.1074/jbc.M002688200 . PMID   10749877.
• Xin H, Stephans JC, Duan X, Harrowe G, Kim E, Grieshammer U, et al. (Jun 2000). "Identification of a novel aspartic-like protease differentially expressed in human breast cancer cell lines". Biochimica et Biophysica Acta. 1501 (2–3): 125–137. 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): 9712–9717. Bibcode:2000PNAS...97.9712F. doi: 10.1073/pnas.160115697 . PMC   16930 . PMID   10931940.
• Iijima K, Ando K, Takeda S, Satoh Y, Seki T, Itohara S, et al. (Sep 2000). "Neuron-specific phosphorylation of Alzheimer's beta-amyloid precursor protein by cyclin-dependent kinase 5". Journal of Neurochemistry. 75 (3): 1085–1091. doi:10.1046/j.1471-4159.2000.0751085.x. PMID   10936190. S2CID   41050912.
• Hussain I, Powell DJ, Howlett DR, Chapman GA, Gilmour L, Murdock PR, et al. (Nov 2000). "ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site". Molecular and Cellular Neurosciences. 16 (5): 609–619. doi:10.1006/mcne.2000.0884. PMID   11083922. S2CID   54379424.
• 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): 23322–23328. 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): 34019–34027. 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): 4687–4693. doi: 10.1074/jbc.M109266200 . PMID   11741910.
• Kim YT, Downs D, Wu S, Dashti A, Pan Y, Zhai P, et al. (Nov 2002). "Enzymic properties of recombinant BACE2". European Journal of Biochemistry. 269 (22): 5668–5677. doi: 10.1046/j.1432-1033.2002.03277.x . PMID   12423367.
• Kondoh K, Tsuji N, Kamagata C, Sasaki M, Kobayashi D, Yagihashi A, et al. (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. S2CID   2195115.

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 .