Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state.

@article{Li2000Presenilin1I,
  title={Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state.},
  author={Y M Li and Ming-tain Lai and M j Xu and Q Huang and Jillian DiMuzio-Mower and Mohita Sardana and X. P. Shi and Kuo-chang Yin and Jules A. Shafer and Stephen J. Gardell},
  journal={Proceedings of the National Academy of Sciences of the United States of America},
  year={2000},
  volume={97 11},
  pages={
          6138-43
        }
}
  • Y. M. Li, M. Lai, S. Gardell
  • Published 23 May 2000
  • Biology, Chemistry
  • Proceedings of the National Academy of Sciences of the United States of America
gamma-Secretase is a membrane-associated protease that cleaves within the transmembrane region of amyloid precursor protein to generate the C termini of the two Abeta peptide isoforms, Abeta40 and Abeta42. Here we report the detergent solubilization and partial characterization of gamma-secretase. The activity of solubilized gamma-secretase was measured with a recombinant substrate, C100Flag, consisting largely of the C-terminal fragment of amyloid precursor protein downstream of the beta… 
Activity-dependent isolation of the presenilin– γ-secretase complex reveals nicastrin and a γ substrate
  • W. Esler, W. Kimberly, M. Wolfe
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 2002
TLDR
Results provide direct biochemical evidence that nicastrin is a member of the active γ-secretase complex, indicate that β-catenin, calsenilin, and presenil in-associated protein are not required for γ activity, and suggest an unprecedented mechanism of substrate–protease interaction.
Purification, pharmacological modulation, and biochemical characterization of interactors of endogenous human gamma-secretase.
TLDR
A fast and convenient multistep purification procedure for isolating endogenous gamma-secretase in considerably high grade is developed, aiding further characterization of this pivotal enzyme and providing evidence that the copurifying proteins identified are unlikely to be part of the active gamma- secretase enzyme.
The Extreme C Terminus of Presenilin 1 Is Essential for γ-Secretase Complex Assembly and Activity*
TLDR
The effects of modifications on the C terminus of PS1 on PS1 endoproteolysis, γ-secretase complex assembly, and activity in cells devoid of endogenous PS are investigated and suggest that the PS1 N- and C-terminal fragment intermolecular interactions are independent of an association with nicastrin and Aph-1.
γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, aph-1, and pen-2
TLDR
It is shown that Aph-1 and Pen-2, two recently identified membrane proteins genetically linked to γ-secretase, associate directly with presenilin and nicastrin in the active protease complex and coassemble to form the active enzyme in mammalian cells.
Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1
Cleavage of amyloid precursor protein (APP) by the β- and γ-secretases generates the amino and carboxy termini, respectively, of the Aβ amyloidogenic peptides Aβ40 and Aβ42—the major constituents of
Deducing the transmembrane domain organization of presenilin-1 in gamma-secretase by cysteine disulfide cross-linking.
TLDR
It is suggested that the conserved cysteines of TMD1 and TMD8 contribute to or allosterically interact with the active site of gamma-secretase, which is an important target for the development of therapeutics for Alzheimer's disease.
Mammalian APH-1 Interacts with Presenilin and Nicastrin and Is Required for Intramembrane Proteolysis of Amyloid-β Precursor Protein and Notch*
TLDR
Using co-immunoprecipitation and nickel affinity pull-down approaches, it is shown that mammalian APH-1, a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain.
γ-Secretase Cleavage Site Specificity Differs for Intracellular and Secretory Amyloid β*
TLDR
The analysis of the subcellular compartments involved in the generation of intracellular Aβ revealed that Aβ is not generated in the early secretory pathway in the human SH-SY5Y neuroblastoma cell line, and demonstrated the existence of an additional factor downstream of the endoplasmic reticulum and early Golgi required for the formation of an active γ-secretase complex.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 23 REFERENCES
Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity
TLDR
The results indicate that the two transmembrane aspartate residues are critical for both presenilin-1 endoproteolysis and γ-secretase activity, and suggest that presenILin 1 is either a unique diaspartyl cofactor for ιsecretase or is itselfγ- secretase, an autoactivated intramembranous aspartyl protease.
Peptidomimetic probes and molecular modeling suggest that Alzheimer's gamma-secretase is an intramembrane-cleaving aspartyl protease.
The amyloid beta-protein (Abeta), implicated in the pathogenesis of Alzheimer's disease (AD), is a proteolytic metabolite generated by the sequential action of beta- and gamma-secretases on the
Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein
TLDR
The results indicate that mutations in PS1 that manifest clinically cause a gain of function and that inhibition of PS1 activity is a potential target for anti-amyloidogenic therapy in Alzheimer's disease.
The Presenilin 1 Protein Is a Component of a High Molecular Weight Intracellular Complex That Contains β-Catenin*
TLDR
Restricted incorporation of the presenilin NTF and CTF along with a potentially functional ligand (β-catenin) into a multimeric complex in the ER and Golgi apparatus may provide an explanation for the regulated accumulation of the NTF or CTF.
A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain
TLDR
It is reported that, in mammalian cells, PS1 deficiency also reduces the proteolytic release of NICD from a truncated Notch construct, thus identifying the specific biochemical step of the Notch signalling pathway that is affected by PS1.
Beta-amyloid precursor protein. Location of transmembrane domain and specificity of gamma-secretase cleavage.
TLDR
Using DNA mutagenesis, this data defines the membrane boundary to position 46/47, a location allowing greater access to carboxyl-terminal processing of beta-amyloid, possibly without membrane destruction.
Characterization of New Polyclonal Antibodies Specific for 40 and 42 Amino Acid-Long Amyloid β Peptides: Their Use to Examine the Cell Biology of Presenilins and the Immunohistochemistry of Sporadic Alzheimer’s Disease and Cerebral Amyloid Angiopathy Cases
TLDR
It is demonstrated that FAD-linked presenilins similarly affect both p342 and Aβ42, suggesting that these mutations misroute the βAPP to a compartment where γ-secretase, but not α- secretase, cleavages are modified.
The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease.
TLDR
Kinetic studies of aggregation by naturally occurring beta protein variants and four model peptides demonstrate that amyloid formation, like crystallization, is a nucleation-dependent phenomenon and suggest that nucleation may be the rate-determining step of in vivo amyloidsogenesis.
Evidence that the 42- and 40-amino acid forms of amyloid beta protein are generated from the beta-amyloid precursor protein by different protease activities.
TLDR
Immunoprecipitating conditioned medium of different cell lines with various A beta 40- and A beta 42-specific antibodies shows a much stronger inhibition of the gamma-secretase cleavage at residue 40 than of that at residue 42, which raises the possibility of identifying compounds that do not interfere with general beta-amyloid precursor protein metabolism, but specifically block the generation of the pathogenic Abeta 42 peptide.
...
1
2
3
...