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Related Concept Videos

Overview of Secretory Vesicles01:33

Overview of Secretory Vesicles

Secretory vesicles, also known as dense core vesicles (DCVs), are membrane-bound vesicles that transport secretory proteins, such as hormones or neurotransmitters. Regulated secretory vesicles transport proteins from the trans-Golgi network to the exterior of the cell. Proteins present in regulated secretory vesicles are required to be rapidly exocytosed in large amounts upon a specific stimulus.
Various proteins regulate the aggregation of molecules inside the secretory vesicles. Chromogranins...
Activation and Inactivation of G Proteins01:22

Activation 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...
The Proteasome Structure01:17

The Proteasome Structure

The ubiquitin-proteasome pathway is a well-known mechanism utilized by eukaryotic cells to remove cytoplasmic proteins that are misfolded, damaged, or no longer needed. In this pathway, the protein that needs to be eliminated undergoes a process called ubiquitination, where a chain of ubiquitin molecules is attached to the 48th lysine residue of the target protein. This ubiquitin modification helps the proteasome distinguish between a target protein and a healthy protein.
The proteasome is an...
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Caspases

Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside cells.
Fusion of Secretory Vesicles with the Plasma Membrane01:26

Fusion of Secretory Vesicles with the Plasma Membrane

Proteins and neurotransmitters in secretory vesicles can be released from a cell upon vesicle docking, priming, and fusion with the plasma membrane. Vesicles are docked and primed in preparation for the quick exocytosis of their contents in response to a stimulus. The fusion process is mainly carried out by a SNAP Receptor or SNARE complex, consisting of synaptobrevin, syntaxin-1, and SNAP-25.
In 1993, Jim Rothman proposed that the antiparallel pairing of vesicular and transmembrane SNAREs, or...
TGF - β Signaling Pathway01:16

TGF - 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...

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Quantitative Measurement of γ-Secretase-mediated Amyloid Precursor Protein and Notch Cleavage in Cell-based Luciferase Reporter Assay Platforms
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Quantitative Measurement of γ-Secretase-mediated Amyloid Precursor Protein and Notch Cleavage in Cell-based Luciferase Reporter Assay Platforms

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Structure and function of gamma-secretase.

Alexandra Tolia1, Bart De Strooper

  • 1Center for Human Genetics, KULeuven and Department for Developmental and Molecular Genetics, VIB, Herestraat 49, 3000 Leuven, Belgium.

Seminars in Cell & Developmental Biology
|November 15, 2008
PubMed
Summary
This summary is machine-generated.

Developing substrate-specific gamma-secretase inhibitors is crucial for Alzheimer's disease treatment. Understanding the enzyme's structure is key to achieving this specificity and advancing drug discovery efforts.

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Area of Science:

  • Biochemistry
  • Neuroscience
  • Pharmacology

Background:

  • Gamma-secretase is a key therapeutic target for Alzheimer's disease.
  • Existing inhibitors are potent but lack substrate specificity due to gamma-secretase's broad substrate range.
  • Structural information is essential for developing targeted therapies.

Purpose of the Study:

  • To review current knowledge on gamma-secretase structure and function.
  • To discuss the implications of structural findings for understanding gamma-secretase's mechanism.
  • To highlight the importance of structural insights for substrate-specific drug development.

Main Methods:

  • Literature review of existing studies on gamma-secretase.
  • Integration of biochemical approaches with structural data from related proteases.
  • Analysis of structure-function relationships.

Main Results:

  • Gamma-secretase's complex structure presents challenges for crystallization.
  • Structural insights are being gained by comparing with other intramembrane-cleaving proteases.
  • Understanding the enzyme's architecture is critical for inhibitor design.

Conclusions:

  • Structural elucidation of gamma-secretase is indispensable for developing specific Alzheimer's disease drugs.
  • Biochemical methods combined with comparative structural analysis are vital.
  • Mechanistic understanding hinges on detailed structural knowledge of this protease.