skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Using N-Terminal Coordination of Cu(II) and Ni(II) to Isolate the Coordination Environment of Cu(I) and Cu(II) Bound to His13 and His14 in Amyloid-$$β$$(4–16)

Journal Article · · Inorganic Chemistry
ORCiD logo [1];  [2];  [3];  [4];  [4]; ORCiD logo [3]
  1. Univ. of Saskatchewan, Saskatoon, SK (Canada)
  2. Saint Mary’s College, Notre Dame, IN (United States); Polish Academy of Sciences, Warsaw (Poland). Inst. of Biochemistry and Biophysics,
  3. Saint Mary’s College, Notre Dame, IN (United States)
  4. SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
+ Show Author Affiliations

The amyloid-β (Aβ) peptide is a cleavage product of the amyloid precursor protein and has been implicated as a central player in Alzheimer’s disease. The N-terminal end of Aβ is variable, and different proportions of these variable-length A βpeptides are present in healthy individuals and those with the disease. The N-terminally truncated form of Aβstarting at position 4 (Aβ4–x) has a His residue as the third amino acid (His6 using the formal Aβ numbering). The N-terminal sequence Xaa-Xaa-His is known as an amino terminal copper and nickel binding motif (ATCUN), which avidly binds Cu(II). This motif is not present in the commonly studied Aβ1–xpeptides. In addition to the ATCUN site, Aβ4–x contains an additional metal binding site located at the tandem His residues (bis-His at His13 and 14) which is also found in other isoforms of Aβ. Using the ATCUN and bis-His motifs, the Aβ4–x peptide is capable of binding multiple metal ions simultaneously. We confirm that Cu(II)bound to this particular ATCUN site is redox silent, but the second Cu(II) site is redox active and can be readily reduced with ascorbate. In this work, we have employed surrogate metal ions to block copper coordination at the ATCUN or the tandem His site in order to isolate spectral features of the copper coordination environment for structural characterization using extended X-ray absorption fine structure (EXAFS) spectroscopy. This approach reveals that each copper coordination environment is independent in the Cu2Aβ4–x state. The identification of two functionally different copper binding environments within theAβ4–x sequence may have important implications for this peptide in vivo.

Research Organization:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); Gordon and Betty Moore Foundation; Preludium Grant; USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH)
Grant/Contract Number:
AC02-76SF00515; GBMF7555.12; 2016/21/N/NZ1/02785; P41GM103393
OSTI ID:
1597744
Journal Information:
Inorganic Chemistry, Vol. 58, Issue 22; ISSN 0020-1669
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 13 works
Citation information provided by
Web of Science

References (73)

Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis journal January 2015
The amyloid hypothesis of Alzheimer's disease at 25 years journal March 2016
Calcium dysregulation in Alzheimer's disease journal March 2008
Calcium hypothesis of Alzheimer’s disease journal October 2009
Dysregulation of Neuronal Iron Homeostasis as an Alternative Unifying Effect of Mutations Causing Familial Alzheimer’s Disease journal August 2018
Role of Copper in the Onset of Alzheimer’s Disease Compared to Other Metals journal January 2018
Copper and Zinc Dysregulation in Alzheimer’s Disease journal December 2018
Copper,  -amyloid, and Alzheimer's disease: Tapping a sensitive connection journal September 2003
Alzheimer’s disease: How metal ions define β-amyloid function journal November 2017
Cellular Functions of the Amyloid Precursor Protein from Development to Dementia journal February 2015
Synaptic vesicle cycle and amyloid β: Biting the hand that feeds journal February 2018
Numerical Simulations Reveal Randomness of Cu(II) Induced Aβ Peptide Dimerization under Conditions Present in Glutamatergic Synapses journal January 2017
Trafficking and Proteolytic Processing of APP journal February 2012
Amyloid plaque core protein in Alzheimer disease and Down syndrome. journal June 1985
Mass spectrometric characterization of brain amyloid beta isoform signatures in familial and sporadic Alzheimer’s disease journal April 2010
Undetectable Intracellular Free Copper: The Requirement of a Copper Chaperone for Superoxide Dismutase journal April 1999
Nerve endings from rat brain tissue release copper upon depolarization. A possible role in regulating neuronal excitability journal August 1989
Methods for studying synaptosomal copper release journal September 2003
A Functional Role for Aβ in Metal Homeostasis? N-Truncation and High-Affinity Copper Binding journal July 2015
The Sub‐picomolar Cu 2+ Dissociation Constant of Human Serum Albumin journal October 2019
Zinc Binding to Alzheimer's Aβ(1–16) Peptide Results in Stable Soluble Complex journal July 2001
The Amyloid-β Peptide of Alzheimer’s Disease Binds Cu I in a Linear Bis-His Coordination Environment: Insight into a Possible Neuroprotective Mechanism for the Amyloid-β Peptide journal December 2008
Iron(II) Binding to Amyloid-β, the Alzheimer’s Peptide journal July 2011
Reevaluation of Copper(I) Affinity for Amyloid-β Peptides by Competition with Ferrozine-An Unusual Copper(I) Indicator journal December 2011
Cu and Zn coordination to amyloid peptides: From fascinating chemistry to debated pathological relevance journal September 2018
Diffraction anomalous fine structure: a new technique for probing local atomic environment journal July 1993
Structural analysis of copper(I) interaction with amyloid β peptide journal June 2019
Importance of dynamical processes in the coordination chemistry and redox conversion of copper amyloid-β complexes journal July 2009
X-ray absorption edge determination of the oxidation state and coordination number of copper. Application to the type 3 site in Rhus vernicifera laccase and its reaction with oxygen journal October 1987
Combined EXAFS and DFT Structure Calculations Provide Structural Insights into the 1:1 Multi-Histidine Complexes of Cu II , Cu I , and Zn II with the Tandem Octarepeats of the Mammalian Prion Protein journal July 2014
Synthesis and X-ray Absorption Spectroscopy Structural Studies of Cu(I) Complexes of HistidylHistidine Peptides:  The Predominance of Linear 2-Coordinate Geometry journal April 2007
Structural Studies of Copper(I) Complexes of Amyloid-β Peptide Fragments: Formation of Two-Coordinate Bis(histidine) Complexes journal November 2008
Copper(i) and copper(ii) binding to β-amyloid 16 (Aβ16) studied by electrospray ionization mass spectrometry journal January 2010
Sequence proximity between Cu(II) and Cu(I) binding sites of human copper transporter 1 model peptides defines reactivity with ascorbate and O2 journal May 2016
How to measure and predict the molar absorption coefficient of a protein journal November 1995
Model Peptide Studies Reveal a Mixed Histidine-Methionine Cu(I) Binding Site at the N-Terminus of Human Copper Transporter 1 journal August 2015
Cryoprotectants Severely Exacerbate X-ray-Induced Photoreduction journal January 2018
Dealing with Cu reduction in X-ray absorption spectroscopy experiments journal January 2019
Cu(II) complexation by “non-coordinating” N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES buffer)☆ journal August 2005
Changes in apparent pH on freezing aqueous buffer solutions and their relevance to biochemical electron-paramagnetic-resonance spectroscopy journal December 1977
Methods and techniques to study the bioinorganic chemistry of metal–peptide complexes linked to neurodegenerative diseases journal October 2012
Metalloprotein active site structure determination: Synergy between X-ray absorption spectroscopy and X-ray crystallography journal October 2012
Real-space multiple-scattering calculation and interpretation of x-ray-absorption near-edge structure journal September 1998
The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals journal July 2007
A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu journal April 2010
Computational studies of Cu(II)[peptide] binding motifs: Cu[HGGG] and Cu[HG] as models for Cu(II) binding to the prion protein octarepeat region journal January 2003
New Insights into Metal Interactions with the Prion Protein: EXAFS Analysis and Structure Calculations of Copper Binding to a Single Octarepeat from the Prion Protein journal October 2013
Continuous surface charge polarizable continuum models of solvation. I. General formalism journal March 2010
Accurate p K a Calculations for Carboxylic Acids Using Complete Basis Set and Gaussian-n Models Combined with CPCM Continuum Solvation Methods journal August 2001
Tuning the Redox Properties of Copper(II) Complexes with Amyloid-β Peptides journal January 2016
Copper binding and redox chemistry of the Aβ16 peptide and its variants: insights into determinants of copper-dependent reactivity journal January 2017
Cu II Binding to Various Forms of Amyloid-β Peptides: Are They Friends or Foes?: Cu II Binding to Various Forms of Amyloid-β Peptides: Are They Friends or Foes? journal October 2017
Conserved Mechanism of Copper Binding and Transfer. A Comparison of the Copper-Resistance Proteins PcoC from Escherichia coli and CopC from Pseudomonas syringae journal May 2007
Structure and Affinity of Cu(I) Bound to Human Serum Albumin journal November 2017
Chemistry and structural studies on the dioxygen-binding copper-1,2-dimethylimidazole system journal December 1993
Acid-catalyzed synthesis of zinc imidazolates and related bimetallic metal-organic framework compounds journal December 2008
Polyoxometalate-Based Metal−Organic Frameworks Assembled under the Ionothermal Conditions journal January 2011
Four New Compounds Constructed from Bis-Antimony-Capped Keggin Polyoxoanions {PMo12Sb2O40} and Different Coordination Fragments journal March 2011
Molecular design to mimic the copper(II) transport site of human albumin. The crystal and molecular structure of copper(II) – glycylglycyl- L -histidine- N -methyl amide monoaquo complex journal April 1976
X-ray and Solution Structures of CuIIGHK and CuIIDAHK Complexes: Influence on Their Redox Properties journal July 2011
Molecular Features of the Copper Binding Sites in the Octarepeat Domain of the Prion Protein journal March 2002
Oxidative decarboxylation of glycylglycyl-L-histidine by copper(II) hydroxide: x-ray structural characterization of .alpha.,.beta.-didehydroglycylglycylhistaminatocopper(II) dihydrate journal February 1978
Proton and Metal Ion Interactions with Glycylglycylhistamine, a Serum Albumin Mimicking Pseudopeptide journal January 1996
A multi-approach study of the interaction of the Cu(II) and Ni(II) ions with alanylglycylhistamine, a mimicking pseudopeptide of the serum albumine N-terminal residue journal May 2005
Amino Terminal Cu(II)- and Ni(II)-Binding (ATCUN) Motif of Proteins and Peptides:  Metal Binding, DNA Cleavage, and Other Properties journal March 1997
Dioxygen-induced decarboxylation and hydroxylation of [Ni II (glycyl-glycyl- L -histidine)] occurs via Ni III : X-ray crystal structure of [Ni II (glycyl-glycyl-α-hydroxy- D , L -histamine)]·3H 2 O journal January 1994
Polarized Cu K-edge XANES of square planar CuCl42− ion. Experimental and theoretical evidence for shake-down phenomena journal December 1984
Ab initio model studies of copper binding to peptides containing a His–His sequence: relevance to the β-amyloid peptide of Alzheimer’s disease journal November 2005
Ab initio modelling of the structure and redox behaviour of copper(I) bound to a His–His model peptide: relevance to the β-amyloid peptide of Alzheimer’s disease journal September 2006
Oxidative stress and the amyloid beta peptide in Alzheimer’s disease journal April 2018
Aqueous Solvation Free Energies of Ions and Ion−Water Clusters Based on an Accurate Value for the Absolute Aqueous Solvation Free Energy of the Proton journal August 2006
An integrated study of the affinities of the Aβ16 peptide for Cu( i ) and Cu( ii ): implications for the catalytic production of reactive oxygen species journal January 2014
Cu(II) Affinity for the Alzheimer’s Peptide: Tyrosine Fluorescence Studies Revisited journal January 2013

Figures / Tables (12)

Scheme 1(p. 2)figure Scheme 1
Figure 1(p. 3)figure Figure 1
Figure 2(p. 5)figure Figure 2
Figure 3(p. 6)figure Figure 3
Figure 4(p. 6)figure Figure 4
Figure 5(p. 7)figure Figure 5
Figure 6(p. 8)figure Figure 6
Table 1(p. 9)table Table 1
Figure 7(p. 10)figure Figure 7
Figure 8(p. 11)figure Figure 8
Figure 9(p. 12)figure Figure 9
Figure 10(p. 13)figure Figure 10

Similar Records

X-ray Absorption Spectroscopy Investigations of Copper(II) Coordination in the Human Amyloid β Peptide
Journal Article · Tue Apr 23 00:00:00 EDT 2019 · Inorganic Chemistry · OSTI ID:1597744
+7 more
Both Met(109) and Met(112) are Utilized for Cu(II) Coordination to the Amyloidogenic Fragment of the Human Prion Protein
Journal Article · Tue Jan 01 00:00:00 EST 2008 · Journal of Inorganic Biochemistry · OSTI ID:1597744
Ni(II) And Co(II) Sensing By Escherichia Coli RcnR
Journal Article · Mon May 18 00:00:00 EDT 2009 · J. Am. Chem. Soc 130:7592,2008 · OSTI ID:1597744
+2 more

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Redox reactions
Peptides and proteins
Metals
Scattering
Extended X-ray absorption fine structure