Structural Studies of the Alzheimer’s Amyloid Precursor Protein Copper-binding Domain Reveal How it Binds Copper Ions
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- 作者：Geoffrey K.-W. Kong ; Julian J. Adams ; Hugh H. Harris ; John F. Boas ; Cyril C. Curtain ; Denise Galatis ; Colin L. Masters ; Kevin J. Barnham ; William J. McKinstry ; Roberto Cappai ; et al.
- 关键词：Alzheimer's disease ; copper-binding protein ; crystallography ; electron paramagnetic resonance ; X-ray absorption spectroscopy
- 刊名：Journal of Molecular Biology
- 出版年：2007
- 出版时间：16 March 2007
- 年：2007
- 卷：367
- 期：1
- 页码：148-161
- 全文大小：1343 K
文摘
Alzheimer's disease (AD) is the major cause of dementia. Amyloid β peptide (Aβ), generated by proteolytic cleavage of the amyloid precursor protein (APP), is central to AD pathogenesis. APP can function as a metalloprotein and modulate copper (Cu) transport, presumably via its extracellular Cu-binding domain (CuBD). Cu binding to the CuBD reduces Aβ levels, suggesting that a Cu mimetic may have therapeutic potential. We describe here the atomic structures of apo CuBD from three crystal forms and found they have identical Cu-binding sites despite the different crystal lattices. The structure of Cu2+-bound CuBD reveals that the metal ligands are His147, His151, Tyr168 and two water molecules, which are arranged in a square pyramidal geometry. The site resembles a Type 2 non-blue Cu center and is supported by electron paramagnetic resonance and extended X-ray absorption fine structure studies. A previous study suggested that Met170 might be a ligand but we suggest that this residue plays a critical role as an electron donor in CuBDs ability to reduce Cu ions. The structure of Cu+-bound CuBD is almost identical to the Cu2+-bound structure except for the loss of one of the water ligands. The geometry of the site is unfavorable for Cu+, thus providing a mechanism by which CuBD could readily transfer Cu ions to other proteins.