Structure of Alzheimer's disease amyloid precursor protein copper-binding domain at atomic resolution

Abstract

Amyloid precursor protein (APP) plays a central role in the pathogenesis of Alzheimer's disease, as its cleavage generates the A peptide that is toxic to cells. APP is able to bind Cu²⁺ and reduce it to Cu⁺ through its copper-binding domain (CuBD). The interaction between Cu²⁺ and APP leads to a decrease in A 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 Cu²⁺ 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 A production.