Open AccessStructure of Alzheimer's disease amyloid precursor protein copper‐binding domain at atomic resolution
Author(s) -
Kong Geoffrey KwaiWai,
Adams Julian J.,
Cappai Roberto,
Parker Michael W.
Publication year - 2007
Publication title -
acta crystallographica section f
Language(s) - English
Resource type - Journals
ISSN - 1744-3091
DOI - 10.1107/s1744309107041139
Subject(s) - copper , cleavage (geology) , chemistry , amyloid precursor protein , peptide , crystallography , amyloid β , fibril , crystal structure , protein structure , pathogenesis , biophysics , amyloid (mycology) , alzheimer's disease , disease , materials science , biochemistry , biology , medicine , inorganic chemistry , pathology , immunology , organic chemistry , fracture (geology) , composite material
Amyloid precursor protein (APP) plays a central role in the pathogenesis of Alzheimer's disease, as its cleavage generates the Aβ peptide that is toxic to cells. APP is able to bind Cu 2+ and reduce it to Cu + through its copper‐binding domain (CuBD). The interaction between Cu 2+ and APP leads to a decrease in Aβ production and to alleviation of the symptoms of the disease in mouse models. Structural studies of CuBD have been undertaken in order to better understand the mechanism behind the process. Here, the crystal structure of CuBD in the metal‐free form determined to ultrahigh resolution (0.85 Å) is reported. The structure shows that the copper‐binding residues of CuBD are rather rigid but that Met170, which is thought to be the electron source for Cu 2+ reduction, adopts two different side‐chain conformations. These observations shed light on the copper‐binding and redox mechanisms of CuBD. The structure of CuBD at atomic resolution provides an accurate framework for structure‐based design of molecules that will deplete Aβ production.