Structure of Alzheimer's disease amyloid precursor protein copper-binding domain at atomic resolution.
Amyloid precursor protein (APP) plays a central role in the pathogenesis of
Alzheimer's disease, as its cleavage generates the Abeta 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 Abeta 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 A) 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 Abeta production.