gamma-secretase

Gamma-secretase (gamma-secretase complex), is an intramembrane aspartyl protease, a protein-shredding enzyme complex and important drug target for Alzheimer's disease (AD). Gamma-secretase cleaves a number of type 1 transmembrane substrates, of which the amyloid precursor protein (APP) and Notch have been the best studied. Thus, APPs undergo sequential proteolytic processing by beta-secretase (BACE1) and gamma-secretase to generate amyloid beta peptides (Aβ). Notch, a protein located as a heterodimeric receptor on the surface of signal-receiving cells, also undergoes a series of proteolytic cleavages. Furthermore, the enzyme cleaves, as far as is currently known, almost a hundred other substrates. How these are recognized and selected is still poorly understood (Lleó A 2008).

Gamma-secretase is formed by proteolysis in the endoplasmic reticulum (ER). The enzyme is then transported to the late ER where it cleaves its substrates. Gamma-secretase is also found in mitochondria, where it plays a supporting role in apoptosis.

Gamma secretase is an enzyme (protein) complex consisting of several subunits. As an integral membrane protein, it is embedded in the lipid layer of the cell membrane.

The protein complex consists of four subunits (Lleó A 2008):

• Nicastrin, a presenilin-1 or -2 homodimer,
• stabilization factor APH-1
• presenilin enhancer 2 (PEN-2).

Since the stabilization factor APH-1 occurs in three isoforms (APH-1A-Long, APH-1A-Short, APH-1B), six different isoforms of gamma-secretase are possible.

Nicastrin (abbreviation NCT) is required for the maturation and transport of the other proteins in the complex, but is not catalytically active itself.

APH-1: APH-1 (anterior pharynx-defective 1) is a protein that was first found in the Notch pathway in Caenorhabditis elegans as a regulator of the localization of nicastrin to the cell surface. Later, APH-1 homologs were identified in other organisms, including humans, where they are part of the gamma-secretase complex. APH-1 and PEN-2 are considered regulators of the maturation process of catalytically active presenilin. APH-1 contains the conserved α-helix binding motif glycine-X-X-X-glycine (short: GXXXG). This is crucial for both the formation and maturation of the gamma-secretase complex.

PEN-2: PEN-2 (short for presenilin enhancer 2) is an integral membrane protein consisting of 101 amino acids. After translation, both the N-terminus and the C-terminus are probably initially located in the lumen of the endoplasmic reticulum and later outside the cell. Both the conserved sequence motif Asp-Tyr-Leu-Ser-Phe at the C-terminus and the total length of the C-terminus are necessary for the formation of the active gamma-secretase complex.

Gamma-secretase is an intramembrane aspartyl protease that cleaves a number of type 1 transmembrane substrates, of which amyloid precursor protein (APP) and Notch are the most commonly studied. Thus, APPs undergo sequential proteolytic processing by beta-secretase (BACE1) and gamma-secretase to generate amyloid beta peptides (Aβ). Notch, a protein located as a heterodimeric receptor on the surface of signal-receiving cells, also undergoes a series of proteolytic cleavages. Furthermore, the enzyme cleaves, as far as is currently known, almost a hundred other substrates. How these are recognized and selected is not yet fully understood (Lleó A 2008).

Defective gamma-secretase cleavage of the amyloid precursor protein APP and Notch can lead to Alzheimer's disease and cancer respectively. Gamma secretase is an important potential drug target for both diseases. Gamma secretase inhibitors (GSIs) and modulators (GSMs) are currently in clinical trials (Yang G et al. 2021).

1. Beel AJ et al. (2008) Substrate specificity of gamma-secretase and other intramembrane proteases. Cell Mol Life Sci 65: 1311-1334
2. Lleó A (2008) . Activity of gamma-secretase on substrates other than APP. Curr Top Med Chem. 2008;8(1):9-16.
3. Yang G et al. (2021) Structural basis of γ-secretase inhibition and modulation by small molecule drugs. Cell 184:521-533.e14.