Prolines and amyloidogenicity in fragments of the Alzheimer's peptide beta/A4.

Although it is well accepted that the structure of amyloid fibrils is dominated by some form of antiparallel beta-sheet, there are few details on the secondary structural arrangements of the constituent peptides and how these peptides pack together in the fibril. We describe here the use of scanning proline mutagenesis to map the secondary structural roles of each residue in amyloidogenic peptide fragments of the Alzheimer's amyloid peptide beta/A4. In two series of fragments related to residues 15-23 and 12-26 of beta/A4, we show that Pro replacement of any residue in the amyloidogenic sequence LVFFAED, corresponding to residues 17-23, leads to essentially complete loss of fibril formation and to excellent peptide solubility. Since peptidyl-prolyl bonds are incapable of forming standard extended chain conformations, the results suggest that residues 17-23 make up the beta-sheet core of the fibrils formed by these fragments. In contrast to the proline replacements, alanine substitutions at residues 17, 18, and 20 have no effect on fibril formation, while replacement of Phe19 reduces fibril formation to 15% of the level found for the wild type sequence. Scanning proline mutagenesis should play a useful role in mapping the secondary structural features of larger amyloidogenic peptide sequences, including longer, physiologically relevant forms of beta/A4. In addition, these results suggest explanations for some amyloidogenic effects observed in disease-related peptides and also suggest a possible role for aggregation-inhibiting insertion of prolines in protein evolution and protein design.

[1]  M J Ball,et al.  beta-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[2]  G Klopman,et al.  Solution structure of residues 1-28 of the amyloid beta-peptide. , 1994, Biochemistry.

[3]  M. Skinner,et al.  In vitro formation of amyloid fibrils from intact beta 2-microglobulin. , 1985, Biochemical and biophysical research communications.

[4]  T. Herning,et al.  Role of proline residues in human lysozyme stability: a scanning calorimetric study combined with X-ray structure analysis of proline mutants. , 1994, Biochemistry.

[5]  J. Reed,et al.  Aggregation and secondary structure of synthetic amyloid βA4 peptides of Alzheimer's disease , 1991 .

[6]  B. Frangione,et al.  Human amyloidosis, Alzheimer disease and related disorders. , 1988, Laboratory investigation; a journal of technical methods and pathology.

[7]  P. Fraser,et al.  Amyloid-like properties of a synthetic peptide corresponding to the carboxy terminus of beta-amyloid protein precursor. , 1992, Archives of biochemistry and biophysics.

[8]  D. Booth,et al.  Human lysozyme gene mutations cause hereditary systemic amyloidosis , 1993, Nature.

[9]  U. Hahn,et al.  Replacement of a cis proline simplifies the mechanism of ribonuclease T1 folding. , 1990, Biochemistry.

[10]  Richard S. Rosenstein,et al.  Intramolecular catalysis of a proline isomerization reaction in the folding of dihydrofolate reductase. , 1992, Biochemistry.

[11]  D. Selkoe,et al.  X-ray diffraction from intraneuronal paired helical filaments and extraneuronal amyloid fibers in Alzheimer disease indicates cross-beta conformation. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[12]  P. S. Kim,et al.  Context is a major determinant of β-sheet propensity , 1994, Nature.

[13]  A. Cohen,et al.  The pathogenesis and biochemistry of amyloidosis , 1987, The Journal of pathology.

[14]  Jeremy M. Berg,et al.  Thermodynamic β -sheet propensities measured using a zinc-finger host peptide , 1993, Nature.

[15]  C. Fierke,et al.  Structure and energetics of a non-proline cis-peptidyl linkage in a proline-202-->alanine carbonic anhydrase II variant. , 1993, Biochemistry.

[16]  L Regan,et al.  A thermodynamic scale for the beta-sheet forming tendencies of the amino acids. , 1994, Biochemistry.

[17]  Y. Sakaki,et al.  Pro----leu change at position 102 of prion protein is the most common but not the sole mutation related to Gerstmann-Sträussler syndrome. , 1989, Biochemical and biophysical research communications.

[18]  S. Prusiner.  Chemistry and biology of prions. , 1992, Biochemistry.

[19]  An SN2 deprotection of synthetic peptides with a low concentration of hydrofluoric acid in dimethyl sulfide: evidence and application in peptide synthesis , 1983 .

[20]  P. S. Kim,et al.  Measurement of the β-sheet-forming propensities of amino acids , 1994, Nature.

[21]  F. Cohen,et al.  Predicted alpha-helical regions of the prion protein when synthesized as peptides form amyloid. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[22]  G. Forloni,et al.  Neurotoxicity of a prion protein fragment , 1993, Nature.

[23]  T. Mizutani,et al.  A new inherited prion disease (PrP‐P105L mutation) showing spastic paraparesis , 1993, Annals of neurology.

[24]  P. Lansbury,et al.  Molecular determinants of amyloid deposition in Alzheimer's disease: conformational studies of synthetic beta-protein fragments. , 1990, Biochemistry.

[25]  J. Pettegrew,et al.  Quantitative evaluation of congo red binding to amyloid-like proteins with a beta-pleated sheet conformation. , 1989, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[26]  C. Barrow,et al.  Solution conformations and aggregational properties of synthetic amyloid beta-peptides of Alzheimer's disease. Analysis of circular dichroism spectra. , 1992, Journal of molecular biology.

[27]  A. Cohen,et al.  Electron Microscopic Observations on a Fibrous Component in Amyloid of Diverse Origins , 1959, Nature.

[28]  J. Ghiso,et al.  In vitro formation of amyloid fibrils from two synthetic peptides of different lengths homologous to Alzheimer's disease β-protein , 1986 .

[29]  E. Kanaya,et al.  Introduction of a non-native disulfide bridge to human lysozyme by cysteine scanning mutagenesis. , 1990, Biochemical and biophysical research communications.

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

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

[32]  A. Clark,et al.  Infrared and laser-Raman spectroscopic studies of thermally-induced globular protein gels. , 2009, International journal of peptide and protein research.

[33]  C. Maury,et al.  Isolation and characterization of cardiac amyloid in familial amyloid polyneuropathy type IV (Finnish): relation of the amyloid protein to variant gelsolin. , 1990, Biochimica et biophysica acta.

[34]  Cooper Jh.  Selective amyloid staining as a function of amyloid composition and structure. Histochemical analysis of the alkaline Congo red, standardized toluidine blue, and iodine methods. , 1974 .

[35]  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.

[36]  M. Skinner,et al.  Characterization of the Amyloid Fibril as a Cross-β Protein∗ , 1969, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[37]  A. Fink,et al.  Nativelike secondary structure in interleukin-1 beta inclusion bodies by attenuated total reflectance FTIR. , 1994, Biochemistry.

[38]  R J Fletterick,et al.  Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[39]  Carl W. Cotman,et al.  In vitro aging of ß-amyloid protein causes peptide aggregation and neurotoxicity , 1991, Brain Research.

[40]  R G Griffin,et al.  An unusual peptide conformation may precipitate amyloid formation in Alzheimer's disease: application of solid-state NMR to the determination of protein secondary structure. , 1991, Biochemistry.

[41]  P. Westermark.  Amyloid and polypeptide hormones: What is their interrelationship? , 1994 .

[42]  D. Selkoe.  The molecular pathology of Alzheimer's disease , 1991, Neuron.

[43]  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.

[44]  M. Benson,et al.  Amyloidosis Related to a λ IV Immunoglobulin Light Chain Protein , 1989 .

[45]  J T Yang,et al.  Calculation of protein conformation from circular dichroism. , 1986, Methods in enzymology.

[46]  M. Stone,et al.  Amyloidosis: a final common pathway for protein deposition in tissues. , 1990, Blood.

[47]  G. Glenner,et al.  X-RAY DIFFRACTION STUDIES ON AMYLOID FILAMENTS , 1968, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[48]  S. Aota,et al.  Molecular cloning and nucleotide sequence of cDNA for murine senile amyloid protein: nucleotide substitutions found in apolipoprotein A-II cDNA of senescence accelerated mouse (SAM). , 1986, Nucleic acids research.

[49]  R. Wetzel.  Mutations and off-pathway aggregation of proteins. , 1994, Trends in biotechnology.

[50]  P. Lansbury,et al.  The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease. , 1993, Biochemistry.

[51]  C. Wernstedt,et al.  A novel peptide in the calcitonin gene related peptide family as an amyloid fibril protein in the endocrine pancreas. , 1986, Biochemical and biophysical research communications.

[52]  J. Reed,et al.  Human and rodent sequence analogs of Alzheimer's amyloid beta A4 share similar properties and can be solubilized in buffers of pH 7.4. , 1991, European journal of biochemistry.

[53]  T. Miyakawa,et al.  Ultrastructure of amyloid fibrils in Alzheimer’s disease and Down’s syndrome , 1986, Virchows Archiv. B, Cell pathology including molecular pathology.

[54]  J. Ghiso,et al.  Amyloid fibrils in hereditary cerebral hemorrhage with amyloidosis of Icelandic type is a variant of gamma-trace basic protein (cystatin C). , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[55]  D. Regoli,et al.  Pharmacology of angiotensin. , 1974, Pharmacological reviews.

[56]  M. Hurle,et al.  A role for destabilizing amino acid replacements in light-chain amyloidosis. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[57]  D. Price,et al.  Amyloidogenesis in Alzheimer's disease: basic biology and animal models , 1992, Current Opinion in Neurobiology.

[58]  Jurg Ott,et al.  Linkage of a prion protein missense variant to Gerstmann–Sträussler syndrome , 1989, Nature.

[59]  M. Pras,et al.  Characterization of High Molecular Weight Amyloid A Proteins , 1991, Scandinavian journal of immunology.

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

[61]  D. Kukuruga,et al.  Purification, ultrastructure, and chemical analysis of Alzheimer disease amyloid plaque core protein. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[62]  K. Sletten,et al.  Fibril in senile systemic amyloidosis is derived from normal transthyretin. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[63]  C. Betsholtz,et al.  Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[64]  B. Frangione,et al.  Ten to fourteen residue peptides of Alzheimer's disease protein are sufficient for amyloid fibril formation and its characteristic x-ray diffraction pattern. , 1987, Biochemical and biophysical research communications.