Structure, Mechanism and Inhibition of γ-Secretase and Presenilin-Like Proteases

Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Biological Chemistry (Impact Factor: 3.27). 08/2010; 391(8):839-47. DOI: 10.1515/BC.2010.086
Source: PubMed


Presenilin is the catalytic component of gamma-secretase, a complex aspartyl protease and a founding member of intramembrane-cleaving proteases. gamma-Secretase is involved in the pathogenesis of Alzheimer's disease and a top target for therapeutic intervention. However, the protease complex processes a variety of transmembrane substrates, including the Notch receptor, raising concerns about toxicity. Nevertheless, gamma-secretase inhibitors and modulators have been identified that allow Notch processing and signaling to continue, and promising compounds are entering clinical trials. Molecular and biochemical studies offer a model for how this protease hydrolyzes transmembrane domains in the confines of the lipid bilayer. Progress has also been made toward structure elucidation of presenilin and the gamma-secretase complex by electron microscopy as well as by studying cysteine-mutant presenilins. The signal peptide peptidase (SPP) family of proteases are distantly related to presenilins. However, the SPPs work as single polypeptides without the need for cofactors and otherwise appear to be simple model systems for presenilin in the gamma-secretase complex. SPP biology, structure, and inhibition will also be discussed.

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    • "However, in contrast to the classical aspartyl proteases, which harbor a D(T/S)G(T/S) active site motif (Pearl and Blundell 1984), the bacterial and archaeal prepilin/prearchaellin peptidases contain two essential aspartyl residues of which the C-terminal aspartate is located in a conserved GxGD motif (LaPointe and Taylor 2000). This family of integral membrane aspartic acid proteases comprises Alzheimer disease-related secretases, signal peptide peptidases (Wolfe 2010) and signal peptide peptidase-like proteases in humans (Voss et al. 2013; Tomita and Iwatsubo 2013) which share the property of the conserved GxGD motif. Though, this group of eukaryotic proteases belongs to the intra-membrane cleaving proteases (I-CLiPs), as their essential aspartyl residues are localized within the transmembrane domains and the cleavage of the substrates occurs inside the membrane (Golde et al. 2009; Fluhrer et al. 2009). "
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    ABSTRACT: In Archaea, type IV prepilins and prearchaellins are processed by designated signal peptidase III (SPaseIII) prior to their incorporation into pili and the archaellum, respectively. These peptidases belong to the family of integral membrane aspartic acid proteases that contain two essential aspartate residues of which the second aspartate is located in a conserved GxGD motif. To this group also bacterial type IV prepilin peptidases, Alzheimer disease-related secretases, signal peptide peptidases and signal peptide peptidase-like proteases in humans belong. Here we have performed detailed in vivo analyses to understand the cleavage activity of PibD, SPaseIII from the thermoacidophilic crenarchaeon Sulfolobus acidocaldarius. Using an already established in vivo heterologous system cleavage assay, we could successfully identify the key amino acid residues essential for catalysis of PibD. Furthermore, in trans complementation of a pibD S. acidocaldarius deletion mutant with PibD variants having substituted key amino acids has consolidated our observations of the importance of these residues in catalysis. Based on our data, we propose to re-define class III peptidases/type IV prepilin/prearchaellin peptidases as GxHyD group (rather than GxGD) of proteases [Hy-hydrophobic amino acid].
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    • "Therefore, it would be interesting to investigate further the role of BACE1 and BACE2, for example by measuring their levels and activities, in both DS and DSAD post-mortem brain samples. Gamma-secretase is as a complex comprising four transmembrane proteins, i.e. presenilin 1/2 (PS1/2), nicastrin (NCT), presenilin enhancer 2 (PEN2), and anterior pharynx-defective 1 (APH1), that assemble into a heteromultimer unit generating and regulating the γsecretase activity293031. Very little is actually known about γ-secretase in DS, while ample literature exists for AD. However, the acute lowering of Aβ synthesis by pharmacological inhibition of γ-secretase improved learning and memory performance in a mouse model of DS [32]. "
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    ABSTRACT: Down syndrome is one of the most common genetic conditions occurring in one in 700 live births. The trisomy of chromosome 21 causes over-expression of APP which in turn is indicated in the increased production of Aβ associated with AD. This makes DS the most common presenile form of AD exceeding PS1 and PS2 FAD. Since a majority of DS individuals develop dementia, it is important to examine whether DS and sporadic AD share common features, for example, to anticipate shared treatments in the future. Here we explore commonalities and differences for secretases and endosomal pathways in DS and AD.
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