The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor
Abstract
Intramembrane proteolysis of transmembrane substrates by the presenilin–γ-secretase complex is preceded and regulated by shedding of the substrate’s ectodomain by α- or β-secretase. We asked whether β- and γ-secretases interact to mediate efficient sequential processing of APP, generating the amyloid β (Aβ) peptides that initiate Alzheimer’s disease. We describe a hitherto unrecognized multiprotease complex containing active β- and γ-secretases. BACE1 coimmunoprecipitated and cofractionated with γ-secretase in cultured cells and in mouse and human brain. An endogenous high molecular weight (HMW) complex (∼5 MD) containing β- and γ-secretases and holo-APP was catalytically active in vitro and generated a full array of Aβ peptides, with physiological Aβ42/40 ratios. The isolated complex responded properly to γ-secretase modulators. Alzheimer’s-causing mutations in presenilin altered the Aβ42/40 peptide ratio generated by the HMW β/γ-secretase complex indistinguishably from that observed in whole cells. Thus, Aβ is generated from holo-APP by a BACE1–γ-secretase complex that provides sequential, efficient RIP processing of full-length substrates to final products.
Overview
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
Verification
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?
Interactions between APP and canonical secretases result in multifunctional APP derivatives.
“The complexity of interactions between APP and canonical secretases results in multifunctional derivatives of APP (Chen et al., 2015; Liu et al., 2019).”
From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Liu et al., 2019
Aη-γ peptides were not detected, probably revealing a lack of functional interaction between η- and γ-secretase.
“Aη-γ peptides, potentially generated by a combined action of MT5-MMP and γ-secretase, were not detected, probably revealing a lack of functional interaction between η- and γ-secretase as it is the case with BACE-1, ADAM10 and γ-secretase (Chen et al., 2015; Liu et al., 2019).”
From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Liu et al., 2019
Replacing the transmembrane domain (TMD) of BACE-1 by that of MT5-MMP did not prevent BACE-1 complex with γ-secretase and Aβ production, suggesting that motifs other than TMD are involved in the formation of the BACE-1/γ-secretase interactions.
“Replacing the transmembrane domain (TMD) of BACE-1 by that of MT5-MMP did not prevent BACE-1 complex with γ-secretase and Aβ production, suggesting that motifs other than TMD are involved in the formation of the BACE-1/γ-secretase interactions (Liu et al., 2019).”
From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Liu et al., 2019
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
The amyloid hypothesis of Alzheimer's disease at 25 years
Selkoe, D. J., & Hardy, J. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606210 · Cited by 6,164
Self-citationAmyloid β-peptide is produced by cultured cells during normal metabolism
Haass, C., Schlossmacher, M. G., Hung, A. Y., Vigo-Pelfrey, C., Mellon, A., Ostaszewski, B. L., Lieberburg, I., Koo, E. H., Schenk, D., Teplow, D. B., et al. (1992) · Nature · doi:10.1038/359322a0 · Cited by 1,921
Self-citationIsolation and quantification of soluble Alzheimer's β-peptide from biological fluids
Seubert, P., Vigo-Pelfrey, C., Esch, F., Lee, M., Dovey, H., Davis, D., Sinha, S., Schiossmacher, M., Whaley, J., Swindlehurst, C., et al. (1992) · Nature · doi:10.1038/359325a0 · Cited by 1,731
Self-citationProduction of the Alzheimer Amyloid β Protein by Normal Proteolytic Processing
Shoji, M., Golde, T. E., Ghiso, J., Cheung, T. T., Estus, S., Shaffer, L. M., Cai, X.-D., McKay, D. M., Tintner, R., Frangione, B., et al. (1992) · Science · doi:10.1126/science.1439760 · Cited by 1,447
Citron, M., Westaway, D., Xia, W., Carlson, G., Diehl, T., Levesque, G., Johnson-wood, K., Lee, M., Seubert, P., Davis, A., et al. (1997) · Nature Medicine · doi:10.1038/nm0197-67 · Cited by 1,271
Self-citationη-Secretase processing of APP inhibits neuronal activity in the hippocampus
Willem, M., Tahirovic, S., Busche, M. A., Ovsepian, S. V., Chafai, M., Kootar, S., Hornburg, D., Evans, L. D. B., Moore, S., Daria, A., et al. (2015) · Nature · doi:10.1038/nature14864 · Cited by 398 · cited 4×
“After aligning the TMDs of BACE1 and MT5-MMP (the identified η-secretase; Willem et al., 2015; Baranger et al., 2016), we generated a chimeric BACE1 molecule by swapping in the TMD of MT5-MMP (Fig.”
BackgroundMethodResultInfluentialTian, Y., Chang, J. C., Fan, E. Y., Flajolet, M., & Greengard, P. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1315110110 · Cited by 233
Additive Effects of PS1 and APP Mutations on Secretion of the 42-Residue Amyloid β-Protein
Citron, M., Eckman, C. B., Diehl, T. S., Corcoran, C., Ostaszewski, B. L., Xia, W., Levesque, G., St. George Hyslop, P., Younkin, S. G., & Selkoe, D. J. (1998) · Neurobiology of Disease · doi:10.1006/nbdi.1998.0183 · Cited by 101
Self-citation
Flagged first, then by citations
Research works printed but not linked: 39
- Bai, 2015, Sampling the conformational space of the catalytic subunit of human γ-secretase, eLife., 4, 1, 10.7554/eLife.11182 · DOI
- Bai, 2015, An atomic structure of human γ-secretase, Nature., 525, 212, 10.1038/nature14892 · DOI
- Baranger, 2016, MT5-MMP, just a new APP processing proteinase in Alzheimer’s disease?, J. Neuroinflammation., 13, 167, 10.1186/s12974-016-0633-4 · DOI
- Bolduc, 2016, Nicastrin functions to sterically hinder γ-secretase-substrate interactions driven by substrate transmembrane domain, Proc. Natl. Acad. Sci. USA., 113, E509, 10.1073/pnas.1512952113 · DOI · Paper page
- Bolduc, 2016, The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase, eLife., 5, 1, 10.7554/eLife.17578 · DOI
- Brown, 2000, Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans, Cell., 100, 391, 10.1016/S0092-8674(00)80675-3 · DOI · Paper page
- Cacquevel, 2008, Rapid purification of active γ-secretase, an intramembrane protease implicated in Alzheimer’s disease, J. Neurochem., 104, 210, 10.1111/j.1471-4159.2007.05041.x · DOI
- Chasseigneaux, 2012, Functions of Aβ, sAPPα and sAPPβ: similarities and differences, J. Neurochem., 120, 99, 10.1111/j.1471-4159.2011.07584.x · DOI
- Chen, 2010, Aph-1 associates directly with full-length and C-terminal fragments of γ-secretase substrates, J. Biol. Chem., 285, 11378, 10.1074/jbc.M109.088815 · DOI
- Chen, 2015, Physical and functional interaction between the α- and γ-secretases: A new model of regulated intramembrane proteolysis, J. Cell Biol., 211, 1157, 10.1083/jcb.201502001 · DOI · Paper page
- Chen, 2006, TMP21 is a presenilin complex component that modulates γ-secretase but not ε-secretase activity, Nature., 440, 1208, 10.1038/nature04667 · DOI
- Crump, 2013, Development and mechanism of γ-secretase modulators for Alzheimer’s disease, Biochemistry., 52, 3197, 10.1021/bi400377p · DOI
- Cui, 2015, Targeting the γ-/β-secretase interaction reduces β-amyloid generation and ameliorates Alzheimer’s disease-related pathogenesis, Cell Discov., 1, 15021, 10.1038/celldisc.2015.21 · DOI
- Edbauer, 2003, Reconstitution of γ-secretase activity, Nat. Cell Biol., 5, 486, 10.1038/ncb960 · DOI
- Ermolieff, 2000, Proteolytic activation of recombinant pro-memapsin 2 (pro-β-secretase) studied with new fluorogenic substrates, Biochemistry., 39, 12450, 10.1021/bi001494f · DOI
- Esler, 2002, Activity-dependent isolation of the presenilin-γ-secretase complex reveals nicastrin and a γ substrate, Proc. Natl. Acad. Sci. USA., 99, 2720, 10.1073/pnas.052436599 · DOI
- Farmery, 2003, Partial purification and characterization of γ-secretase from post-mortem human brain, J. Biol. Chem., 278, 24277, 10.1074/jbc.M211992200 · DOI
- Fraering, 2004, Detergent-dependent dissociation of active γ-secretase reveals an interaction between Pen-2 and PS1-NTF and offers a model for subunit organization within the complex, Biochemistry., 43, 323, 10.1021/bi035748j · DOI
- Fraering, 2004, Purification and characterization of the human γ-secretase complex, Biochemistry., 43, 9774, 10.1021/bi0494976 · DOI
- Gu, 2004, The presenilin proteins are components of multiple membrane-bound complexes that have different biological activities, J. Biol. Chem., 279, 31329, 10.1074/jbc.M401548200 · DOI
- Haapasalo, 2011, The many substrates of presenilin/γ-secretase, J. Alzheimers Dis., 25, 3, 10.3233/JAD-2011-101065 · DOI · Paper page
- Jumpertz, 2012, Presenilin is the molecular target of acidic γ-secretase modulators in living cells, PLoS One., 7, e30484, 10.1371/journal.pone.0030484 · DOI
- Kimberly, 2003, γ-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2, Proc. Natl. Acad. Sci. USA., 100, 6382, 10.1073/pnas.1037392100 · DOI
- Kornilova, 2005, The initial substrate-binding site of γ-secretase is located on presenilin near the active site, Proc. Natl. Acad. Sci. USA., 102, 3230, 10.1073/pnas.0407640102 · DOI
- Li, 2000, Presenilin 1 is linked with γ-secretase activity in the detergent solubilized state, Proc. Natl. Acad. Sci. USA., 97, 6138, 10.1073/pnas.110126897 · DOI
- Li, 2000, Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1, Nature., 405, 689, 10.1038/35015085 · DOI · Paper page
- Li, 2014, Structural interactions between inhibitor and substrate docking sites give insight into mechanisms of human PS1 complexes, Structure., 22, 125, 10.1016/j.str.2013.09.018 · DOI
- Martin, 2008, Regulated intramembrane proteolysis of Bri2 (Itm2b) by ADAM10 and SPPL2a/SPPL2b, J. Biol. Chem., 283, 1644, 10.1074/jbc.M706661200 · DOI
- Muratore, 2017, Cell-type Dependent Alzheimer’s Disease Phenotypes: Probing the Biology of Selective Neuronal Vulnerability, Stem Cell Reports., 9, 1868, 10.1016/j.stemcr.2017.10.015 · DOI
- Ran, 2013, Genome engineering using the CRISPR-Cas9 system, Nat. Protoc., 8, 2281, 10.1038/nprot.2013.143 · DOI · Paper page
- Rawson, 1997, Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs, Mol. Cell., 1, 47, 10.1016/S1097-2765(00)80006-4 · DOI · Paper page
- Reinhard, 2005, The amyloid-β precursor protein: integrating structure with biological function, EMBO J., 24, 3996, 10.1038/sj.emboj.7600860 · DOI
- Sato, 2006, Structure of the catalytic pore of γ-secretase probed by the accessibility of substituted cysteines, J. Neurosci., 26, 12081, 10.1523/JNEUROSCI.3614-06.2006 · DOI
- Sun, 2015, Structural basis of human γ-secretase assembly, Proc. Natl. Acad. Sci. USA., 112, 6003, 10.1073/pnas.1506242112 · DOI
- Takasugi, 2003, The role of presenilin cofactors in the γ-secretase complex, Nature., 422, 438, 10.1038/nature01506 · DOI
- Tomita, 1998, Cleavage of Alzheimer’s amyloid precursor protein (APP) by secretases occurs after O-glycosylation of APP in the protein secretory pathway. Identification of intracellular compartments in which APP cleavage occurs without using toxic agents that interfere with protein metabolism, J. Biol. Chem., 273, 6277, 10.1074/jbc.273.11.6277 · DOI
- Vassar, 2014, Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects, J. Neurochem., 130, 4, 10.1111/jnc.12715 · DOI · Paper page
- Wakabayashi, 2009, Analysis of the γ-secretase interactome and validation of its association with tetraspanin-enriched microdomains, Nat. Cell Biol., 11, 1340, 10.1038/ncb1978 · DOI · Paper page
- Wolfe, 1999, Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity, Nature., 398, 513, 10.1038/19077 · DOI
Cited by
Sorted by citations
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204
García-González, L., Pilat, D., Baranger, K., & Rivera, S. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00244 · Cited by 88
Metadata
- Authors
- Liu, L., Ding, L., Rovere, M., Wolfe, M. S., & Selkoe, D. J.
- Affiliations
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 1
- University of Kansas School of Pharmacy, Department of Medical Chemistry, Lawrence, KS 2
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2019-01-09
- Volume
- 218
- Issue
- 2
- Pages
- 644-663
- ISSN
- 0021-9525
- 1540-8140
- PMC
- PMC6363461
- Cited by
- 64
- References
- 8
- Language
- en
- Funders
- National Institutes of Health (R01 AG06173, P01 AG015379)
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
