Related Experiment Video

Updated: May 2, 2026

Purification and Aggregation of the Amyloid Precursor Protein Intracellular Domain
10:08

Purification and Aggregation of the Amyloid Precursor Protein Intracellular Domain

Published on: August 28, 2012

11.4K

How amyloid precursor protein protects itself from cleavage

Hsiang-Kai Lin1, Patrick C A van der Wel1

  • 1Department of Structural Biology, University of Pittsburgh School of Medicine, Biomedical Science Tower 3, 3501 Fifth Avenue, Pittsburgh, PA 15260, USA.

Structure (London, England : 1993)
|March 11, 2014
PubMed

Insights

The Flemish mutation in amyloid precursor protein (APP) alters its structure and influences the production of amyloid-beta (Aβ) peptides. This study reveals how extracellular elements and cholesterol impact APP processing by γ-secretase.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Amyloid precursor protein (APP) processing is central to neurodegenerative diseases.
  • The Flemish mutation in APP is linked to altered Aβ peptide generation.
  • γ-secretase activity is crucial for APP cleavage.

Purpose of the Study:

  • To investigate the structural impact of the Flemish mutation on APP.
  • To elucidate how this mutation affects APP cleavage by γ-secretase.
  • To understand the role of extracellular elements and cholesterol in Aβ peptide formation.

Main Methods:

  • Structural analysis of APP with the Flemish mutation.
  • Biochemical assays to assess γ-secretase activity.
  • Molecular modeling to study cholesterol interactions.

Main Results:

  • The Flemish mutation induces specific conformational changes in APP.
  • An extracellular inhibitory element and cholesterol modulate γ-secretase cleavage site accessibility.
  • These factors influence the production ratio of different Aβ peptides.

Conclusions:

  • The Flemish mutation affects APP conformation, influencing its interaction with γ-secretase.
  • Cholesterol and extracellular interactions are critical regulators of APP processing.
  • Understanding these mechanisms provides insight into Aβ peptide generation in disease contexts.

More Related Videos

Imaging the Intracellular Trafficking of APP with Photoactivatable GFP07:55

Imaging the Intracellular Trafficking of APP with Photoactivatable GFP

Published on: October 17, 2015

10.7K
A11-positive β-amyloid Oligomer Preparation and Assessment Using Dot Blotting Analysis06:17

A11-positive β-amyloid Oligomer Preparation and Assessment Using Dot Blotting Analysis

Published on: May 22, 2018

11.1K

Related Concept Videos

Amyloid Fibrils03:03

Amyloid Fibrils

Amyloid fibrils are aggregates of misfolded proteins.  Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils. 
Amyloid deposits were observed as early as 1639 in the liver and the spleen.   In 1854, Rudolph Virchow performed iodine staining,...
10.2K
Amyloid Fibrils03:03

Amyloid Fibrils

5.2K
Protein Folding01:25

Protein Folding

Proteins are chains of amino acids linked together by peptide bonds. Upon synthesis, a protein folds into a three-dimensional conformation, critical to its biological function. Interactions between its constituent amino acids guide protein folding, and hence the protein structure is primarily dependent on its amino acid sequence.
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...
8.8K
Protein Folding01:22

Protein Folding

Overview
112.3K
Mitochondrial Precursor Proteins01:39

Mitochondrial Precursor Proteins

Mitochondrial precursors are partially unfolded or loosely folded polypeptide chains. Newly synthesized precursors are inhibited from spontaneously folding into their native conformation by the cytosolic chaperones, heat shock proteins 70 (Hsp70), and mitochondrial import stimulation factors (MSFs). Precursors bound to MSFs are guided to the TOM70-TOM37 receptors, while precursors bound to Hsp70  chaperones are targetted to TOM20-TOM22 receptor complexes.
Most of the mitochondrial...
2.9K
Protein Folding Quality Check in the RER01:29

Protein Folding Quality Check in the RER

ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
4.4K