Zinc binding to Alzheimer's Abeta(1-16) peptide results in stable soluble complex.

Aggregation of the human amyloid beta-peptide (Abeta) into insoluble plaques is a key event in Alzheimer's disease. Zinc sharply accelerates the Abeta aggregation in vitro, and the Abeta region 6-28 was suggested to be the obligatory zinc binding site. However, time-dependent aggregation of the zinc-bound Abeta species investigated so far prevented their structural analysis. By using CD spectroscopy, we have shown here for the first time that (i) the protected synthetic peptide spanning the fragment 1-16 of Abeta binds specifically zinc with 1:1 and 1:2 stoichiometry under physiologically relevant conditions; (ii) the peptide-zinc complex is soluble and stable for several months; (iii) zinc binding causes a conformational change of the peptide towards a more structured state. These findings suggest the region 1-16 to be the minimal autonomous zinc binding domain of Abeta.

[1]  Carl W. Cotman,et al.  Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[2]  C. Barrow,et al.  Solution structures of beta peptide and its constituent fragments: relation to amyloid deposition. , 1991, Science.

[3]  T. Darden,et al.  An Atomic Model for the Pleated β-Sheet Structure of Aβ Amyloid Protofilaments , 1999 .

[4]  Xudong Huang,et al.  Zinc-induced Alzheimer’s Aβ1–40 Aggregation Is Mediated by Conformational Factors* , 1997, The Journal of Biological Chemistry.

[5]  D. Kirschner,et al.  Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. , 1990, Science.

[6]  G. Fasman.  Circular Dichroism and the Conformational Analysis of Biomolecules , 1996, Springer US.

[7]  R. Wetzel,et al.  Aggregation state and neurotoxic properties of Alzheimer beta-amyloid peptide. , 1995, Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration.

[8]  P E Fraser,et al.  Structure of beta-crystallite assemblies formed by Alzheimer beta-amyloid protein analogues: analysis by x-ray diffraction. , 1993, Biophysical journal.

[9]  D. Selkoe,et al.  Translating cell biology into therapeutic advances in Alzheimer's disease , 1999, Nature.

[10]  M. Ball,et al.  Chemical characterization of A beta 17-42 peptide, a component of diffuse amyloid deposits of Alzheimer disease. , 1994, The Journal of biological chemistry.

[11]  J. Kelly,et al.  The alternative conformations of amyloidogenic proteins and their multi-step assembly pathways. , 1998, Current opinion in structural biology.

[12]  Synthetic peptide homologous to beta protein from Alzheimer disease forms amyloid-like fibrils in vitro. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[13]  M. Mattson.  Untangling the pathophysio-chemistry of β-amyloid , 1995, Nature Structural Biology.

[14]  C. Masters,et al.  Rapid induction of Alzheimer A beta amyloid formation by zinc. , 1994, Science.

[15]  D. Teplow,et al.  Structural and kinetic features of amyloid beta-protein fibrillogenesis. , 1998, Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis.

[16]  H. Shao,et al.  Solution structures of micelle-bound amyloid beta-(1-40) and beta-(1-42) peptides of Alzheimer's disease. , 1999, Journal of molecular biology.

[17]  P. Fraser,et al.  pH-dependent structural transitions of Alzheimer amyloid peptides. , 1991, Biophysical journal.

[18]  B. Yankner,et al.  Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Eric J. Simon,et al.  Structural model for the β-amyloid fibril based on interstrand alignment of an antiparallel-sheet comprising a C-terminal peptide , 1995, Nature Structural Biology.

[20]  C. Barrow,et al.  Histidine-13 is a crucial residue in the zinc ion-induced aggregation of the A beta peptide of Alzheimer's disease. , 1999, Biochemistry.

[21]  R. Tanzi,et al.  Modulation of A beta adhesiveness and secretase site cleavage by zinc. , 1994, The Journal of biological chemistry.

[22]  K. Grzeschik,et al.  The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor , 1987, Nature.

[23]  J. Berg,et al.  Lessons from zinc-binding peptides. , 1997, Annual review of biophysics and biomolecular structure.

[24]  S. Estus,et al.  Production of the Alzheimer amyloid beta protein by normal proteolytic processing. , 1992, Science.

[25]  P E Wright,et al.  Peptide models of protein folding initiation sites. 1. Secondary structure formation by peptides corresponding to the G- and H-helices of myoglobin. , 1993, Biochemistry.

[26]  P. V. von Hippel,et al.  Calculation of protein extinction coefficients from amino acid sequence data. , 1989, Analytical biochemistry.

[27]  I. Lieberburg,et al.  Cellular mechanisms of beta-amyloid production and secretion. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[28]  D. Kirschner,et al.  Structural analysis of Alzheimer's beta(1-40) amyloid: protofilament assembly of tubular fibrils. , 1998, Biophysical journal.

[29]  P. Lansbury,et al.  Amyloid fibrillogenesis: themes and variations. , 2000, Current opinion in structural biology.

[30]  H. Zeng,et al.  Methodological and chemical factors affecting amyloid beta peptide amyloidogenicity. , 1999, Methods in enzymology.

[31]  H. Takeuchi,et al.  Metal binding modes of Alzheimer's amyloid beta-peptide in insoluble aggregates and soluble complexes. , 2000, Biochemistry.

[32]  D. Selkoe,et al.  Amyloid β-peptide is produced by cultured cells during normal metabolism , 1992, Nature.

[33]  K. Beyreuther,et al.  Structure of amyloid A4-(1-40)-peptide of Alzheimer's disease. , 1995, European journal of biochemistry.

[34]  M. Citron,et al.  Aβ-Generating Enzymes Recent Advances in β- and γ-Secretase Research , 2000, Neuron.

[35]  M. Hurle,et al.  Prolines and amyloidogenicity in fragments of the Alzheimer's peptide beta/A4. , 1995, Biochemistry.

[36]  T. Benzinger,et al.  Propagating structure of Alzheimer’s β-amyloid(10–35) is parallel β-sheet with residues in exact register , 1998 .

[37]  O. Gursky,et al.  Temperature-dependent β-sheet formation in β-amyloid Aβ1–40 peptide in water: uncoupling β-structure folding from aggregation , 2000 .

[38]  D. Westaway,et al.  Examining the zinc binding site of the amyloid-β peptide , 2000 .

[39]  K. Berndt,et al.  Solution structure of a naturally-occurring zinc-peptide complex demonstrates that the N-terminal zinc-binding module of the Lasp-1 LIM domain is an independent folding unit. , 1996, Biochemistry.

[40]  J. Reed,et al.  Substitutions of hydrophobic amino acids reduce the amyloidogenicity of Alzheimer's disease beta A4 peptides. , 1992, Journal of molecular biology.

[41]  E. Rojas,et al.  Zn2+ interaction with Alzheimer amyloid beta protein calcium channels. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[42]  D. Selkoe,et al.  Isolation and quantification of soluble Alzheimer's β-peptide from biological fluids , 1992, Nature.

[43]  R. Tanzi,et al.  Alzheimer's disease, beta-amyloid protein and zinc. , 2000, The Journal of nutrition.

[44]  L. Serrano,et al.  De novo design and structural analysis of a model β-hairpin peptide system , 1996, Nature Structural Biology.

[45]  D. Craik,et al.  Solution structure of amyloid beta-peptide(1-40) in a water-micelle environment. Is the membrane-spanning domain where we think it is? , 1998, Biochemistry.