Abstract
Described as the “proteasome of the membrane” or the “scissors in the membrane,” γ-secretase has notoriously complicated biology, and even after decades of research, the full extent of its regulatory mechanism remains unclear. γ-Secretase is an intramembrane aspartyl protease complex composed of four obligatory subunits: Nicastrin (NCT), Presenilin (PS), Presenilin Enhancer-2 (Pen-2), and Anterior pharynx-defective-1 (Aph-1). γ-Secretase cleaves numerous type 1 transmembrane substrates, with no apparent homology, and plays major roles in broad biological pathways such as development, neurogenesis, and cancer. Notch and the amyloid precursor protein (APP) and are undoubtedly the best-studied γ-secretase substrates because of their role in cancer and Alzheimer’s disease (AD) and therefore became the focus of increasing studies as an attractive therapeutic target. The regulation of γ-secretase is intricate and involves the function of multiple cellular entities. Recently, γ-secretase modulatory proteins (GSMPs), which are non-essential subunits and yet modulate γ-secretase activity and specificity, have emerged as an important component in guiding γ-secretase. GSMPs are responsive to cellular and environmental changes and therefore, provide another layer of regulation of γ-secretase. This type of enzymatic regulation allows for a rapid and fine-tuning of γ-secretase activity when appropriate signals appear enabling a temporal level of regulation. In this review article, we discuss the latest developments on GSMPs and implications on the development of effective therapeutics for γ-secretase-associated diseases such as AD and cancer.
Highlights
Described as the “proteasome of the membrane” or the “scissors in the membrane,” γsecretase has notoriously complicated biology, and even after decades of research, the full extent of its regulatory mechanism remains unclear. γ-Secretase is an intramembrane aspartyl protease complex composed of four obligatory subunits: Nicastrin (NCT), Presenilin (PS), Presenilin Enhancer-2 (Pen-2), and Anterior pharynx-defective-1 (Aph1). γ-Secretase cleaves numerous type 1 transmembrane substrates, with no apparent homology, and plays major roles in broad biological pathways such as development, neurogenesis, and cancer
(2) Cultured neurons isolated from PS1-deficient mice produce significantly less Aβ and amyloid precursor protein (APP) fragments that are not processed by γ-secretase is being accumulated (Naruse et al, 1998; De Strooper et al, 1998). (3) γ-Secretase activity is abolished in cells cultured from PS1 and PS2 deficient mice (Herreman et al, 2000; Zhang et al, 2000). (4) γ-Secretase activity is reduced by mutagenesis of two conserved aspartate residues in the transmembrane regions of PS1 (Wolfe et al, 1999). (5) γ-Secretase activity is connected to PS-containing macromolecular complexes (Li et al, 2000a)
GSAP that is associated with Alzheimer’s disease (AD), which might associate GSAP as a disease-related risk factor (Zhu et al, 2014; Perez et al, 2017)
Summary
Described as the “proteasome of the membrane” or the “scissors in the membrane,” γsecretase has notoriously complicated biology, and even after decades of research, the full extent of its regulatory mechanism remains unclear. γ-Secretase is an intramembrane aspartyl protease complex composed of four obligatory subunits: Nicastrin (NCT), Presenilin (PS), Presenilin Enhancer-2 (Pen-2), and Anterior pharynx-defective-1 (Aph1). γ-Secretase cleaves numerous type 1 transmembrane substrates, with no apparent homology, and plays major roles in broad biological pathways such as development, neurogenesis, and cancer. Notch and the amyloid precursor protein (APP) and are undoubtedly the best-studied γ-secretase substrates because of their role in cancer and Alzheimer’s disease (AD) and became the focus of increasing studies as an attractive therapeutic target.
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