Related Experiment Video
Updated: Jul 19, 2026
06:40
Quantitative Measurement of γ-Secretase-mediated Amyloid Precursor Protein and Notch Cleavage in Cell-based Luciferase Reporter Assay Platforms
Published on: January 25, 2018
Assembly, trafficking and function of gamma-secretase.
Christoph Kaether1, Christian Haass, Harald Steiner
1Laboratory for Alzheimer's and Parkinson's Disease Research, Department of Biochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, Munich, Germany. ckaether@fli-leibniz.de
Neuro-Degenerative Diseases
|October 19, 2006
Summary
Gamma-secretase, crucial for Alzheimer's disease pathology, is a four-protein complex. Its assembly involves presenilin, nicastrin, PEN-2, and APH-1, with specific domains regulating trafficking and function.
Area of Science:
- Molecular Biology
- Neuroscience
- Biochemistry
Background:
- Gamma-secretase cleaves beta-amyloid precursor protein, producing amyloid-beta, a key component in Alzheimer's disease.
- Understanding gamma-secretase's structure and function is vital for developing Alzheimer's disease therapeutics.
Purpose of the Study:
- To review the identification, assembly, and trafficking of the gamma-secretase complex.
- To elucidate the roles of individual subunits and regulatory factors in gamma-secretase function.
Main Methods:
- Reconstitution experiments to determine essential components.
- Green fluorescent protein (GFP) tagging for cellular localization.
- Knockdown and knockout studies to investigate complex assembly pathways.
- Domain mapping for assembly and trafficking.
Main Results:
- Gamma-secretase comprises presenilin (PS), nicastrin (NCT), PEN-2, and APH-1, sufficient for protease activity.
- PS is a catalytic subunit belonging to the GxGD aspartyl protease family.
- Complex assembly occurs sequentially: NCT and APH-1 stabilize PS, followed by PEN-2.
- Distinct human gamma-secretase complexes exist, involving PS1/PS2 and APH-1a/APH-1b variants.
- Localization studies identified PS and gamma-secretase activity at the plasma membrane and endosomes.
- Rer1 acts as an auxiliary factor, binding PEN-2 to aid complex assembly.
Conclusions:
- The gamma-secretase complex is a multi-subunit protease essential for amyloid-beta production.
- A detailed model for gamma-secretase assembly and trafficking has been established.
- Identification of Rer1 as an auxiliary factor provides new insights into complex regulation.
More Related Videos
Related Concept Videos
01:30Assembly of Signaling Complexes
Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
01:16TGF - β Signaling Pathway
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
02:33Hedgehog Signaling Pathway
The Hedgehog gene (Hh) was first discovered due to its control of the growth of disorganized, hair-like bristles phenotype in Drosophila, much like hedgehog spines. Hh plays a crucial role in the development of organs and the maintenance of homeostasis in both invertebrates and vertebrates. However, while Drosophila has only one Hh protein, mammals have multiple functional Hedgehog proteins - Sonic (Shh), Desert (Dhh), and Indian Hedgehog (Ihh). All of these homologous proteins have adapted to...
02:33Hedgehog Signaling Pathway
The Hedgehog gene (Hh) was first discovered due to its control of the growth of disorganized, hair-like bristles phenotype in Drosophila, much like hedgehog spines. Hh plays a crucial role in the development of organs and the maintenance of homeostasis in both invertebrates and vertebrates. However, while Drosophila has only one Hh protein, mammals have multiple functional Hedgehog proteins - Sonic (Shh), Desert (Dhh), and Indian Hedgehog (Ihh). All of these homologous proteins have adapted to...
01:22Activation and Inactivation of G Proteins
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high affinity and are together...
01:22Amplifying Signals via Enzymatic Cascade
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...