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Title: Structural Studies of the Alzheimer's Amyloid Precursor Protein Copper-binding Domain Reveal How it Binds Copper Ions

Authors:
; ; ; ; ; ; ; ; ; ;  [1];  [2];  [2];  [2]
  1. Sydney
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
DOE - BASIC ENERGY SCIENCES
OSTI Identifier:
1169981
Resource Type:
Journal Article
Resource Relation:
Journal Name: J. Mol. Biol.; Journal Volume: 367; Journal Issue: (1) ; 03, 2007
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Kong, Geoffrey K.-W., Adams, Julian J., Harris, Hugh H., Boas, John F., Curtain, Cyril C., Galatis, Denise, Masters, Colin L., Barnham, Kevin J., McKinstry, William J., Cappai, Roberto, Parker, Michael W., Melbourne), Monash), and SVIMR-A). Structural Studies of the Alzheimer's Amyloid Precursor Protein Copper-binding Domain Reveal How it Binds Copper Ions. United States: N. p., 2015. Web. doi:10.1016/j.jmb.2006.12.041.
Kong, Geoffrey K.-W., Adams, Julian J., Harris, Hugh H., Boas, John F., Curtain, Cyril C., Galatis, Denise, Masters, Colin L., Barnham, Kevin J., McKinstry, William J., Cappai, Roberto, Parker, Michael W., Melbourne), Monash), & SVIMR-A). Structural Studies of the Alzheimer's Amyloid Precursor Protein Copper-binding Domain Reveal How it Binds Copper Ions. United States. doi:10.1016/j.jmb.2006.12.041.
Kong, Geoffrey K.-W., Adams, Julian J., Harris, Hugh H., Boas, John F., Curtain, Cyril C., Galatis, Denise, Masters, Colin L., Barnham, Kevin J., McKinstry, William J., Cappai, Roberto, Parker, Michael W., Melbourne), Monash), and SVIMR-A). Fri . "Structural Studies of the Alzheimer's Amyloid Precursor Protein Copper-binding Domain Reveal How it Binds Copper Ions". United States. doi:10.1016/j.jmb.2006.12.041.
@article{osti_1169981,
title = {Structural Studies of the Alzheimer's Amyloid Precursor Protein Copper-binding Domain Reveal How it Binds Copper Ions},
author = {Kong, Geoffrey K.-W. and Adams, Julian J. and Harris, Hugh H. and Boas, John F. and Curtain, Cyril C. and Galatis, Denise and Masters, Colin L. and Barnham, Kevin J. and McKinstry, William J. and Cappai, Roberto and Parker, Michael W. and Melbourne) and Monash) and SVIMR-A)},
abstractNote = {},
doi = {10.1016/j.jmb.2006.12.041},
journal = {J. Mol. Biol.},
number = (1) ; 03, 2007,
volume = 367,
place = {United States},
year = {Fri Feb 06 00:00:00 EST 2015},
month = {Fri Feb 06 00:00:00 EST 2015}
}
  • 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 aremore » 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.« less
  • The binding of Cu{sup 2+} ions to the copper-binding domain of the amyloid precursor protein of Alzheimer’s disease reduces the production of the amyloid β peptide, which is centrally involved in Alzheimer’s disease. Structural studies of the copper-binding domain will provide a basis for structure-based drug design that might prove useful in treating this devastating disease. Alzheimer’s disease is thought to be triggered by production of the amyloid β (Aβ) peptide through proteolytic cleavage of the amyloid precursor protein (APP). The binding of Cu{sup 2+} to the copper-binding domain (CuBD) of APP reduces the production of Aβ in cell-culture andmore » animal studies. It is expected that structural studies of the CuBD will lead to a better understanding of how copper binding causes Aβ depletion and will define a potential drug target. The crystallization of CuBD in two different forms suitable for structure determination is reported here.« less
  • Highlights: • Copper levels are elevated in the tumour microenvironment. • APP mitigates copper-induced growth inhibition of DU145 prostate cancer (PCa) cells. • The APP intracellular domain is a prerequisite; soluble forms have no effect. • The E1 CuBD of APP is also a prerequisite. • APP copper binding potentially mitigates copper-induced PCa cell growth inhibition. - Abstract: Copper plays an important role in the aetiology and growth of tumours and levels of the metal are increased in the serum and tumour tissue of patients affected by a range of cancers including prostate cancer (PCa). The molecular mechanisms that enablemore » cancer cells to proliferate in the presence of elevated copper levels are, therefore, of key importance in our understanding of tumour growth progression. In the current study, we have examined the role played by the amyloid precursor protein (APP) in mitigating copper-induced growth inhibition of the PCa cell line, DU145. A range of APP molecular constructs were stably over-expressed in DU145 cells and their effects on cell proliferation in the presence of copper were monitored. Our results show that endogenous APP expression was induced by sub-toxic copper concentrations in DU145 cells and over-expression of the wild-type protein was able to mitigate copper-induced growth inhibition via a mechanism involving the cytosolic and E1 copper binding domains of the full-length protein. APP likely represents one of a range of copper binding proteins that PCa cells employ in order to ensure efficient proliferation despite elevated concentrations of the metal within the tumour microenvironment. Targeting the expression of such proteins may contribute to therapeutic strategies for the treatment of cancers.« less
  • 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 themore » 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.« less
  • The amyloid {beta}-peptide deposit found in the brain tissue of patients with Alzheimer disease is derived from a large heparin-binding protein precursor APP. The biological function of APP and its homologs is not precisely known. Here we report the x-ray structure of the E2 domain of APL-1, an APP homolog in Caenorhabditis elegans, and compare it to the human APP structure. We also describe the structure of APL-1 E2 in complex with sucrose octasulfate, a highly negatively charged disaccharide, which reveals an unexpected binding pocket between the two halves of E2. Based on the crystal structure, we are able tomore » map, using site-directed mutagenesis, a surface groove on E2 to which heparin may bind. Our biochemical data also indicate that the affinity of E2 for heparin is influenced by pH: at pH 5, the binding appears to be much stronger than that at neutral pH. This property is likely caused by histidine residues in the vicinity of the mapped heparin binding site and could be important for the proposed adhesive function of APL-1.« less