Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

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

29.09.2008
New experiments reveal detailed physical features of a protein thought to exacerbate the pathology of Alzheimer’s disease

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 â peptide (Aâ), the primary component of amyloid plaques found in the brains of patients with Alzheimer’s disease.

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.

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 Aâ production,” says Nukina.

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 â protein production. Molecular and Cellular Biology 28, 3663–3671 (2008).

Saeko Okada | ResearchSEA
Further information:
http://www.rikenresearch.riken.jp/research/541/
http://www.researchsea.com

More articles from Studies and Analyses:

nachricht Real-time feedback helps save energy and water
08.02.2017 | Otto-Friedrich-Universität Bamberg

nachricht The Great Unknown: Risk-Taking Behavior in Adolescents
19.01.2017 | Max-Planck-Institut für Bildungsforschung

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Impacts of mass coral die-off on Indian Ocean reefs revealed

21.02.2017 | Earth Sciences

Novel breast tomosynthesis technique reduces screening recall rate

21.02.2017 | Medical Engineering

Use your Voice – and Smart Homes will “LISTEN”

21.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>