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).
The Great Unknown: Risk-Taking Behavior in Adolescents
19.01.2017 | Max-Planck-Institut für Bildungsforschung
A sudden drop in outdoor temperature increases the risk of respiratory infections
11.01.2017 | University of Gothenburg
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
20.01.2017 | Awards Funding
20.01.2017 | Materials Sciences
20.01.2017 | Life Sciences