Structure of Alzheimer’s disease amyloid precursor protein copper-binding domain at atomic resolution
- Biota Structural Biology Laboratory, St Vincent’s Institute, 9 Princes Street, Fitzroy, Victoria 3065 (Australia)
- Department of Pathology and Centre for Neuroscience, The University of Melbourne, Victoria 3010 (Australia)
An atomic resolution structure of the copper-binding domain of the Alzheimer’s disease amyloid precursor protein is presented. 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{sup 2+} and reduce it to Cu{sup +} through its copper-binding domain (CuBD). The interaction between Cu{sup 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{sup 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.
- OSTI ID:
- 22360403
- Journal Information:
- Acta Crystallographica. Section F, Vol. 63, Issue Pt 10; Other Information: PMCID: PMC2339725; PMID: 17909280; PUBLISHER-ID: fw5140; OAI: oai:pubmedcentral.nih.gov:2339725; Copyright (c) International Union of Crystallography 2007; Country of input: International Atomic Energy Agency (IAEA); ISSN 1744-3091
- Country of Publication:
- United Kingdom
- Language:
- English
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