Biology:Beta-secretase 2

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Short description: Enzyme found in humans

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Beta-secretase 2 (EC 3.4.23.45, also known as memapsin-1) is an enzyme[1][2][3][4] 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.[4]

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.[5]

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.[6] 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.[7]

Interactions

BACE2 has been shown to interact with GGA1[8] and GGA2.[8]

References

  1. ↑ "Specificity of memapsin 1 and its implications on the design of memapsin 2 (beta-secretase) inhibitor selectivity". Biochemistry 41 (27): 8742–8746. July 2002. doi:10.1021/bi025926t. PMID 12093293. 
  2. ↑ "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. Sep 2000. doi:10.1159/000015608. PMID 10965118. 
  3. ↑ "The DNA sequence of human chromosome 21". Nature 405 (6784): 311–319. May 2000. doi:10.1038/35012518. PMID 10830953. Bibcode: 2000Natur.405..311H. 
  4. ↑ 4.0 4.1 "Entrez Gene: BACE2 beta-site APP-cleaving enzyme 2". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=25825. 
  5. ↑ "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. Jun 2013. doi:10.1073/pnas.1220748110. PMID 23754390. Bibcode: 2013PNAS..11010658R. 
  6. ↑ "Bace2 is a β cell-enriched protease that regulates pancreatic β cell function and mass". Cell Metabolism 14 (3): 365–377. 2011-09-07. doi:10.1016/j.cmet.2011.06.018. ISSN 1932-7420. PMID 21907142. 
  7. ↑ *"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). Mar 2024. doi:10.1073/pnas.2317430121. PMID 38437540. Bibcode: 2024PNAS..12117430G. 
  8. ↑ 8.0 8.1 "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. Jul 2002. doi:10.1016/S0014-5793(02)03052-1. PMID 12135764. Bibcode: 2002FEBSL.524..183H. 

Further reading



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