Article

Gamma-secretase: structure, function, and modulation for Alzheimer's disease.

Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
Current topics in medicinal chemistry (Impact Factor: 3.45). 02/2008; 8(1):2-8.
Source: PubMed

ABSTRACT Gamma-secretase proteolyzes a variety of membrane-associated fragments derived from type I integral membrane proteins, including the amyloid beta-protein precursor, involved in Alzheimer's disease, and the Notch receptor, critical for cellular differentiation. This protease is composed of four integral membrane proteins: presenilin, nicastrin, Aph-1 and Pen-2. Assembly of these four components leads to presenilin autoproteolysis into two subunits, each of which contributes one aspartate to the active site of an aspartyl protease. The protease contains an initial docking site for substrate, where it binds prior to passing between the two presenilin subunits to the internal water-containing active site. The extracellular region of nicastrin also interacts with the N-terminus of the substrate as an essential step in substrate recognition and processing. Modulation of APP processing without interfering with Notch signaling is an important therapeutic goal, and allosteric sites on the protease allow such selective modulation. A better structural and mechanistic understanding of gamma-secretase should ultimately allow structure-based design of more potent and selective modulators.

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    • "These findings suggest a pathway for γ-secretase substrate from docking site to active site: upon binding to the outer surface of presenilin at the NTF/CTF interface, the substrate can pass between these two presenilin subunits to access the internal active site. γ-Secretase has in many ways been an attractive target for Alzheimer therapeutics (Wolfe, 2008), with one inhibitor (compound 3, Figure 2) now in advanced clinical trials (Siemers et al., 2007). However, interference with Notch processing and signalling may lead to toxicities that preclude clinical use of such inhibitors. "
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    ABSTRACT: 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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    • "This is in sharp contrast to mice with deficiencies in components of the γ-secretase complex [52]. For example, mice deficient in presenilin-1 [53], nicastrin [54], or APH-1 [55] all exhibit serious developmental defects and die at early embryonic stages because γ-secretase is required to process Notch, a signaling molecule that controls cell fate in embryonic and adult myelopoiesis [56] [57] [58]. Therefore, compared with γ-secretase, BACE1 is viewed as a better drug target whose inhibition should cause less serious biological dysfunction. "
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