Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein
10.1073/pnas.97.4.1456
Crossref journal-article
Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences (341)
Abstract

The cDNAs of two new human membrane-associated aspartic proteases, memapsin 1 and memapsin 2, have been cloned and sequenced. The deduced amino acid sequences show that each contains the typical pre , pro , and aspartic protease regions, but each also has a C-terminal extension of over 80 residues, which includes a single transmembrane domain and a C-terminal cytosolic domain. Memapsin 2 mRNA is abundant in human brain. The protease domain of memapsin 2 cDNA was expressed in Escherichia coli and was purified. Recombinant memapsin 2 specifically hydrolyzed peptides derived from the β-secretase site of both the wild-type and Swedish mutant β-amyloid precursor protein (APP) with over 60-fold increase of catalytic efficiency for the latter. Expression of APP and memapsin 2 in HeLa cells showed that memapsin 2 cleaved the β-secretase site of APP intracellularly. These and other results suggest that memapsin 2 fits all of the criteria of β-secretase, which catalyzes the rate-limiting step of the in vivo production of the β-amyloid (Aβ) peptide leading to the progression of Alzheimer's disease. Recombinant memapsin 2 also cleaved a peptide derived from the processing site of presenilin 1, albeit with poor kinetic efficiency. Alignment of cleavage site sequences of peptides indicates that the specificity of memapsin 2 resides mainly at the S 1 ′ subsite, which prefers small side chains such as Ala, Ser, and Asp.

Bibliography

Lin, X., Koelsch, G., Wu, S., Downs, D., Dashti, A., & Tang, J. (2000). Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein. Proceedings of the National Academy of Sciences, 97(4), 1456–1460.

Authors 6
  1. Xinli Lin (first)
  2. Gerald Koelsch (additional)
  3. Shili Wu (additional)
  4. Debbie Downs (additional)
  5. Azar Dashti (additional)
  6. Jordan Tang (additional)
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Dates
Type When
Created 23 years, 1 month ago (July 26, 2002, 10:38 a.m.)
Deposited 3 years, 2 months ago (June 7, 2022, 1:11 a.m.)
Indexed 2 weeks, 6 days ago (Aug. 7, 2025, 4:57 p.m.)
Issued 25 years, 6 months ago (Feb. 15, 2000)
Published 25 years, 6 months ago (Feb. 15, 2000)
Published Online 25 years, 6 months ago (Feb. 15, 2000)
Published Print 25 years, 6 months ago (Feb. 15, 2000)
Funders 0

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@article{Lin_2000, title={Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein}, volume={97}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.97.4.1456}, DOI={10.1073/pnas.97.4.1456}, number={4}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Lin, Xinli and Koelsch, Gerald and Wu, Shili and Downs, Debbie and Dashti, Azar and Tang, Jordan}, year={2000}, month=feb, pages={1456–1460} }