Article

Presenilin: Running with Scissors in the Membrane

Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Cell (Impact Factor: 33.12). 11/2007; 131(2):215-21. DOI: 10.1016/j.cell.2007.10.012
Source: PubMed

ABSTRACT The presenilin-containing gamma-secretase complex is an unusual membrane-embedded protease that processes a wide variety of integral membrane proteins, clearing protein stubs from the lipid bilayer and participating in critical signaling pathways. The protease is also central to Alzheimer's disease and certain cancers and is therefore an important therapeutic target. Here we highlight recent progress in deciphering the role of presenilin/gamma-secretase in biology and medicine and pose key questions for future study.

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    • "The β-secretase is also called BACE1 (β-site amyloid precursor protein cleaving enzyme 1), which is an important enzyme in development of AD pathology. BACE1 cleaves transmembrane APP between residues 671 and 672, and carboxy-terminal fragment of APP is cleaved by γ-secretase, facilitating intramembrane proteolysis by the presenilin 1 (PSEN1) and presenilin 2 (PSEN2) [14, 15]. Subsequently the small 4 kilodalton of amyloid-Aβ1-40 and Aβ1-42 is generated by sequential β and γ-secretase cleavage of APP. "
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    ABSTRACT: The β-site APP cleaving enzyme 1 (BACE1) is an important target for causing Alzheimer's disease (AD), due to the brain deposition peptide amyloid beta (Aβ) require cleavages of amyloid precursor protein (APP) by BACE1 and γ-secretase, but treatments of AD still have side effect in recent therapy. This study utilizes the world largest traditional Chinese medicine (TCM) database and database screening to provide potential BACE1 inhibited compound. Molecular dynamics (MD) simulation was carried out to observe the dynamics structure after ligand binding. We found that Triptofordin B1 has less toxicity than pyrimidine analogue, which has more potent binding affinity with BACE1. For trajectory analysis, all conformations are tending to be stable during 5000 ps simulation time. In dynamic protein validation, the residues of binding region are still stable after MD simulation. For snapshot comparison, we found that Triptofordin B1 could reduce the binding cavity; the results reveal that Triptofordin B1 could bind to BACE1 and better than control, which could be used as potential lead drug to design novel BACE1 inhibitor for AD therapy.
    BioMed Research International 05/2014; 2014(3):741703. DOI:10.1155/2014/741703 · 2.71 Impact Factor
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    • "γ-Secretase is also an aspartyl protease, although it is a complex of four integral membrane proteins and completely unrelated to soluble or membrane-tethered proteases [24]. Nevertheless, inhibitors of γ-secretase were more easily identified and several of these advanced into the clinic much more quickly than inhibitors of BACE1. "
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    ABSTRACT: Brain deposition of the amyloid beta-protein (A β ) and tau are characteristic features in Alzheimer's disease (AD). Mutations in the A β precursor protein (APP) and a protease involved in A β production from APP strongly argue for a pathogenic role of A β in AD, while mutations in tau are associated with related disorders collectively called frontotemporal lobar degeneration (FTLD). Despite intense effort, therapeutic strategies that target A β or tau have not yet yielded medications, suggesting that alternative approaches should be pursued. In recent years, our laboratory has studied the role of mRNA in AD and FTLD, specifically those encoding tau and the A β -producing protease BACE1. As many FTLD-causing tau mutations destabilize a hairpin structure that regulates RNA splicing, we have targeted this structure with small molecules, antisense oligonucleotides, and small molecule-antisense conjugates. We have also discovered that microRNA interaction with the 3'-untranslated region of tau regulates tau expression. Regarding BACE1, we found that alternative splicing leads to inactive splice isoforms and antisense oligonucleotides shift splicing toward these inactive isoforms to decrease A β production. In addition, a G-quadruplex structure in the BACE1 mRNA plays a role in splice regulation. The prospects for targeting tau and BACE1 mRNAs as therapeutic strategies will be discussed.
    04/2014; 2014(5):757549. DOI:10.1155/2014/757549
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    • "These senile plaques are extracellular deposits composed of aggregated peptides called Ab (Selkoe 1991). The proteolytic action of both b-and c-secretase results in the Ab peptide formation which is then secreted into the extracellular milieu (Selkoe 2004; Haass and Selkoe 2007; Selkoe and Wolfe 2007). The Ab peptide accumulation was caused due to overproduction or inefficient clearance and defects in the proteolytic degradation (Tanzi et al. 2004). "
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    ABSTRACT: Amyloid beta (Aβ) peptides play a central role in the pathogenesis of Alzheimer's disease. The accumulation of Aβ peptides in AD brain was caused due to overproduction or insufficient clearance and defects in the proteolytic degradation of Aβ peptides. Hence, Aβ peptide degradation could be a promising therapeutic approach in AD treatment. Recent experimental report suggests that aminopeptidase from Streptomyces griseus KK565 (SGAK) can degrade Aβ peptides but the interactive residues are yet to be known in detail at the atomic level. Hence, we developed the three-dimensional model of aminopeptidase (SGAK) using SWISS-MODEL, Geno3D and MODELLER. Model built by MODELLER was used for further studies. Molecular docking was performed between aminopeptidase (SGAK) with wild-type and mutated Aβ peptides. The docked complex of aminopeptidase (SGAK) and wild-type Aβ peptide (1IYT.pdb) shows more stability than the other complexes. Molecular docking and MD simulation results revealed that the residues His93, Asp105, Glu139, Glu140, Asp168 and His255 are involved in the hydrogen bonding with Aβ peptide and zinc ions. The interactions between carboxyl oxygen atoms of Glu139 of aminopeptidase (SGAK) with water molecule suggest that the Glu139 may be involved in the nucleophilic attack on Ala2-Glu3 peptide bond of Aβ peptide. Hence, amino acid Glu139 of aminopeptidase (SGAK) might play an important role to degrade Aβ peptides, a causative agent of Alzheimer's disease.
    Amino Acids 04/2014; 46(8). DOI:10.1007/s00726-014-1740-0 · 3.65 Impact Factor
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