Nanotechnology Now

Our NanoNews Digest Sponsors



Heifer International

Wikipedia Affiliate Button


android tablet pc

Home > Press > Structural ‘snapshots’ of a protein implicated in Alzheimer’s disease

Figure 1: Schematic depicting generation of Aβ from APP. γ-secretase is another enzyme involved in the process. AD, Alzheimer’s disease.
Figure 1: Schematic depicting generation of Aβ from APP. γ-secretase is another enzyme involved in the process. AD, Alzheimer’s disease.

Abstract:
New experiments reveal detailed physical features of a protein thought to exacerbate the pathology of Alzheimer's disease

Structural ‘snapshots’ of a protein implicated in Alzheimer’s disease

Japan | Posted on September 25th, 2008

A recent study describes the structure of the active form of BACE1, which is an enzyme implicated in Alzheimer's disease. BACE1 cleaves amyloid precursor protein (APP), thereby releasing amyloid β peptide (Aβ), the primary component of amyloid plaques found in the brains of patients with Alzheimer's disease (Fig. 1).

As amyloid plaques are thought by many to inflict brain cell damage that results in Alzheimer's disease, efforts are under way to design drugs to inhibit the activity of BACE1. Complicating these efforts is the fact that BACE1 seems to cleave APP in vesicles called endosomes, which sport a pH much more acidic than that of other areas of the cell or the extracellular fluid.

Structures of several BACE1 complexes have been solved using a technique called x-ray crystallography, wherein structural information is gleaned from x-rays diffracted from crystallized versions of proteins. However, never before has a structural view of active BACE1 been available. In a paper recently published in Molecular and Cellular Biology, Nobuyuki Nukina and colleagues from the RIKEN Brain Science Institute in Wako and the RIKEN SPring-8 Center in Harima present and analyze crystals of active BACE11.

To identify conditions in which crystallized BACE1 is active, the researchers soaked BACE1 crystals in acidic (pH 4.0, 4.5 and 5.0) and neutral (pH 7.0) solutions, together with synthetic APP peptides engineered to fluoresce after cleavage. In agreement with data localizing BACE1 activity to acidic endosomes, crystallized BACE1 cleaved APP at acidic but not neutral pH.
photo

Video 1: Shape changes associated with activation of BACE1.

High resolution video and legend

Comparative analyses revealed substantial differences in the shape of BACE1 crystals soaked in acidic and neutral solutions, suggesting that BACE1 undergoes structural rearrangements during activation (Vid. 1). Most notable was the position of the ‘flap' covering the active site of BACE1, which was open and closed in acidic and neutral crystals, respectively. Also observed were marked changes in the shape of the BACE1 site at which the substrate—in this case, APP—binds.

Binding of a water molecule—thought to be important in the chemical reaction through which BACE1 cleaves APP—became weaker as the pH was lowered. Whether BACE1 exists as a mix of hydrated active and dehydrated inactive forms in endosomes remains unclear.

These findings highlight the importance of considering environmental factors such as pH in structure-based design of enzyme inhibitors. "The structure of the active form of BACE1 identified here should be used for developing drugs to regulate Aβ production," says Nukina.
Reference

1. Shimizu, H., Tosaki, A., Kaneko, K., Hisano, T., Sakurai, T. & Nukina, N. Crystal structure of an active form of BACE1, an enzyme responsible for amyloid β protein production. Molecular and Cellular Biology 28, 3663-3671 (2008).

####

For more information, please click here

Copyright © Riken

If you have a comment, please Contact us.

Issuers of news releases, not 7th Wave, Inc. or Nanotechnology Now, are solely responsible for the accuracy of the content.

Bookmark:
Delicious Digg Newsvine Google Yahoo Reddit Magnoliacom Furl Facebook

Related Links

article

Related News Press

News and information

SEMATECH to Showcase Innovation and Advances in Manufacturing at SEMICON Japan 2014: SEMATECH experts will share the latest techniques, emerging trends and best practices in advanced manufacturing strategies and methodologies November 26th, 2014

Australian startup creates world’s first 100% cotton hydrophobic T-Shirts November 26th, 2014

The mysterious 'action at a distance' between liquid containers November 26th, 2014

'Giant' charge density disturbances discovered in nanomaterials: Juelich researchers amplify Friedel oscillations in thin metallic films November 26th, 2014

Nanomedicine

Vegetable oil ingredient key to destroying gastric disease bacteria: In mice, therapeutic nanoparticles dampen H. pylori bacteria and inflammation that lead to ulcers and gastric cancer November 25th, 2014

Research reveals how our bodies keep unwelcome visitors out of cell nuclei November 24th, 2014

ASU, IBM move ultrafast, low-cost DNA sequencing technology a step closer to reality November 24th, 2014

An Inside Job: UC-Designed Nanoparticles Infiltrate, Kill Cancer Cells From Within November 24th, 2014

Discoveries

The mysterious 'action at a distance' between liquid containers November 26th, 2014

'Giant' charge density disturbances discovered in nanomaterials: Juelich researchers amplify Friedel oscillations in thin metallic films November 26th, 2014

Vegetable oil ingredient key to destroying gastric disease bacteria: In mice, therapeutic nanoparticles dampen H. pylori bacteria and inflammation that lead to ulcers and gastric cancer November 25th, 2014

Research yields material made of single-atom layers that snap together like Legos November 25th, 2014

Announcements

SEMATECH to Showcase Innovation and Advances in Manufacturing at SEMICON Japan 2014: SEMATECH experts will share the latest techniques, emerging trends and best practices in advanced manufacturing strategies and methodologies November 26th, 2014

Australian startup creates world’s first 100% cotton hydrophobic T-Shirts November 26th, 2014

The mysterious 'action at a distance' between liquid containers November 26th, 2014

'Giant' charge density disturbances discovered in nanomaterials: Juelich researchers amplify Friedel oscillations in thin metallic films November 26th, 2014

NanoNews-Digest
The latest news from around the world, FREE




  Premium Products
NanoNews-Custom
Only the news you want to read!
 Learn More
NanoTech-Transfer
University Technology Transfer & Patents
 Learn More
NanoStrategies
Full-service, expert consulting
 Learn More












ASP
Nanotechnology Now Featured Books




NNN

The Hunger Project







© Copyright 1999-2014 7th Wave, Inc. All Rights Reserved PRIVACY POLICY :: CONTACT US :: STATS :: SITE MAP :: ADVERTISE