Crystal Structure of an Active Form of BACE1, an Enzyme Responsible for Amyloid β Protein Production
Open accessAbstract
BACE1 (beta-secretase) is a transmembrane aspartic protease that cleaves the beta-amyloid precursor protein and generates the amyloid beta peptide (Abeta). BACE1 cycles between the cell surface and the endosomal system many times and becomes activated interconvertibly during its cellular trafficking, leading to the production of Abeta. Here we report the crystal structure of the catalytically active form of BACE1. The active form has novel structural features involving the conformation of the flap and subsites that promote substrate binding. The functionally essential residues and water molecules are well defined and play a key role in the iterative activation of BACE1. We further describe the crystal structure of the dehydrated form of BACE1, showing that BACE1 activity is dependent on the dynamics of a catalytically required Asp-bound water molecule, which directly affects its catalytic properties. These findings provide insight into a novel regulation of BACE1 activity and elucidate how BACE1 modulates its activity during cellular trafficking.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
BACE1 activity is optimal at acidic pH.
“As a type-1 transmembrane aspartyl protease, BACE1 activity is optimal at acidic pH (Shimizu et al., 2008)”
From Distinct anterograde trafficking pathways of BACE1 and amyloid precursor protein from the TGN and the regulation of amyloid-β production (2020) · cites this paper as Shimizu et al., 2008
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864 · see citing works
Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., et al. (1999) · Science · doi:10.1126/science.286.5440.735 · Cited by 3,876 · cited 3× · see citing works
“In fact, APP cleavage by -secretase is reported to occur in all of these compartments (4, 16, 17, 20, 36).”
Background
Flagged first, then by citations
Research works printed but not linked: 1
- [20]20. Lin, X., G. Koelsch, S. Wu, D. Downs, A. Dashti, and J. Tang. 2000. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc. Natl. Acad. Sci. USA 97: 1456-1460.
Cited by
Sorted by citations
Sharma, P., Srivastava, P., Seth, A., Tripathi, P. N., Banerjee, A. G., & Shrivastava, S. K. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.12.006 · Cited by 331 · see citing works
Yuan, J., Venkatraman, S., Zheng, Y., McKeever, B. M., Dillard, L. W., & Singh, S. B. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm301659n · Cited by 135 · see citing works
Tan, J. Z. A., Fourriere, L., Wang, J., Perez, F., Boncompain, G., & Gleeson, P. A. (2020) · Molecular Biology of the Cell · doi:10.1091/mbc.e19-09-0487 · Cited by 37 · see citing works
Dual Inhibitors of AChE and BACE-1 for Reducing Aβ in Alzheimer’s Disease: From In Silico to In Vivo
Stern, N., Gacs, A., Tátrai, E., Flachner, B., Hajdú, I., Dobi, K., Bágyi, I., Dormán, G., Lőrincz, Z., Cseh, S., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113098 · Cited by 35 · see citing works
Is It the Twilight of BACE1 Inhibitors?
Hrabinova, M., Pejchal, J., Kucera, T., Jun, D., Schmidt, M., & Soukup, O. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200503023323 · Cited by 28 · see citing works
Nadh, A. G., Revikumar, A., Sudhakaran, P. R., & Nair, A. S. (2022) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2022.105422 · Cited by 22 · see citing works
- Authors
- Shimizu, H., Tosaki, A., Kaneko, K., Hisano, T., Sakurai, T., & Nukina, N.
- Affiliations
- RIKEN Center for Brain Science (JP)
- SPring-8 (JP)
- Corresponding author
- Nukina, Nobuyuki
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2008-06-01
- Volume
- 28
- Issue
- 11
- Pages
- 3663-3671
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2423307
- OpenAlex
- W2096584150
- Cited by
- 205
- References
- 2
- Citations by year
- 2026: 14 · 2025: 7 · 2024: 23 · 2023: 11 · 2022: 19 · 2021: 13 · 2020: 8 · 2019: 17 · 2018: 10 · 2017: 13 · 2016: 14 · 2015: 11 · 2014: 12 · 2013: 9 · 2012: 5
- FWCI
- 4.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- BACE1, beta-secretase, amyloid-beta, amyloid precursor protein, aspartic protease, enzyme activation, flap conformation, substrate binding site, catalytic water molecule, protein trafficking, Alzheimer's disease
- MeSH terms
- Aspartic Acid, Binding Sites, Catalysis, Enzyme Activation, Enzyme Inhibitors, Humans, Hydrogen-Ion Concentration, Oligopeptides, Protein Conformation, Recombinant Proteins, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Crystallography, X-Ray, Catalytic Domain, Amyloid Precursor Protein Secretases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
