Structural Studies of the Alzheimer's Amyloid Precursor Protein Copper-Binding Domain Reveal How It Binds Copper Ions

Journal Article · Mon Jul 09 04:00:00 EDT 2007 · J. Mol. Biol. 367:148,2007

DOI:https://doi.org/10.1016/j.jmb.2006.12.041· OSTI ID:909814

Kong, G K.-W.; Adams, J J; Harris, H H; Boas, J F; Curtain, C C; Galatis, D; Master, C L; Barnham, K J; McKinstry, W J; Cappai, R; Parker, M W

Alzheimer's disease (AD) is the major cause of dementia. Amyloid {beta} peptide (A {beta}), 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 A{beta} 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 Cu[2+]-bound CuBD reveals that the metal ligands are His147, His151, Tyrl68 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 Cu[2+]-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.

• Research Organization: Stanford Linear Accelerator Center (SLAC)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC02-76SF00515
• OSTI ID: 909814
• Report Number(s): SLAC-REPRINT-2007-080
• Journal Information: J. Mol. Biol. 367:148,2007, Journal Name: J. Mol. Biol. 367:148,2007 Vol. 367; ISSN JMOBAK; ISSN 0022-2836
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
74 ATOMIC AND MOLECULAR PHYSICS
BINDING ENERGY
COPPER
COPPER IONS
CRYSTAL LATTICES
ELECTRON SPIN RESONANCE
FINE STRUCTURE
Other
OTHER
PRECURSOR
PROTEINS