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• W1994560730 abstract "Although amyloid fibrils deposit with various proteins, the comprehensive mechanism by which they form remains unclear. We studied the formation of fibrils of human islet amyloid polypeptide associated with type II diabetes in the presence of various concentrations of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) under acidic and neutral pH conditions using CD, amyloid-specific thioflavin T fluorescence, fluorescence imaging with thioflavin T, and atomic force microscopy. At low pH, the formation of fibrils was promoted by HFIP with an optimum at 5% (v/v). At neutral pH in the absence of HFIP, significant amounts of amorphous aggregates formed in addition to the fibrils. The addition of HFIP suppressed the formation of amorphous aggregates, leading to a predominance of fibrils with an optimum effect at 25% (v/v). Under both conditions, higher concentrations of HFIP dissolved the fibrils and stabilized the α-helical structure. The results indicate that fibrils and amorphous aggregates are different types of precipitates formed by exclusion from water-HFIP mixtures. The exclusion occurs through the combined effects of hydrophobic interactions and electrostatic interactions, both of which are strengthened by low concentrations of HFIP, and a subtle balance between the two types of interactions determines whether the fibrils or amorphous aggregates dominate. We suggest a general view of how the structure of precipitates varies dramatically from single crystals to amyloid fibrils and amorphous aggregates. Although amyloid fibrils deposit with various proteins, the comprehensive mechanism by which they form remains unclear. We studied the formation of fibrils of human islet amyloid polypeptide associated with type II diabetes in the presence of various concentrations of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) under acidic and neutral pH conditions using CD, amyloid-specific thioflavin T fluorescence, fluorescence imaging with thioflavin T, and atomic force microscopy. At low pH, the formation of fibrils was promoted by HFIP with an optimum at 5% (v/v). At neutral pH in the absence of HFIP, significant amounts of amorphous aggregates formed in addition to the fibrils. The addition of HFIP suppressed the formation of amorphous aggregates, leading to a predominance of fibrils with an optimum effect at 25% (v/v). Under both conditions, higher concentrations of HFIP dissolved the fibrils and stabilized the α-helical structure. The results indicate that fibrils and amorphous aggregates are different types of precipitates formed by exclusion from water-HFIP mixtures. The exclusion occurs through the combined effects of hydrophobic interactions and electrostatic interactions, both of which are strengthened by low concentrations of HFIP, and a subtle balance between the two types of interactions determines whether the fibrils or amorphous aggregates dominate. We suggest a general view of how the structure of precipitates varies dramatically from single crystals to amyloid fibrils and amorphous aggregates. IntroductionAmyloid fibrils play an important role in a range of diseases, including Alzheimer's disease, dialysis-related amyloidosis, and type II diabetes mellitus (1Sipe J.D. Crit. Rev. Clin. Lab. Sci. 1994; 31: 325-354Crossref PubMed Scopus (189) Google Scholar, 2Dobson C.M. Nature. 2003; 426: 884-890Crossref PubMed Scopus (3701) Google Scholar, 3Selkoe D.J. Nat. Cell Biol. 2004; 6: 1054-1061Crossref PubMed Scopus (700) Google Scholar, 4Yamamoto S. Gejyo F. Biochim. Biophys. Acta. 2005; 1753: 4-10Crossref PubMed Scopus (70) Google Scholar). In addition, various proteins and peptides not related to amyloidosis form similar fibrillar deposits in vitro (5Chiti F. Dobson C.M. Annu. Rev. Biochem. 2006; 75: 333-366Crossref PubMed Scopus (5041) Google Scholar). In several cases, the fibrillar deposits are functional (6Fowler D.M. Koulov A.V. Balch W.E. Kelly J.W. Trends Biochem. Sci. 2007; 32: 217-224Abstract Full Text Full Text PDF PubMed Scopus (824) Google Scholar, 7Maji S.K. Perrin M.H. Sawaya M.R. Jessberger S. Vadodaria K. Rissman R.A. Singru P.S. Nilsson K.P. Simon R. Schubert D. Eisenberg D. Rivier J. Sawchenko P. Vale W. Riek R. Science. 2009; 325: 328-332Crossref PubMed Scopus (750) Google Scholar). Although the biological impact of amyloid fibrils is tremendous, we still do not have a general view of why and how the fibrils form. On the other hand, we have increasing evidence suggesting the underlying mechanism of fibril formation. 1) First, fibril formation is coupled with the denaturation of proteins (8Kelly J.W. Curr. Opin. Struct. Biol. 1998; 8: 101-106Crossref PubMed Scopus (946) Google Scholar, 9Khurana R. Gillespie J.R. Talapatra A. Minert L.J. Ionescu-Zanetti C. Millett I. Fink A.L. Biochemistry. 2001; 40: 3525-3535Crossref PubMed Scopus (288) Google Scholar, 10Raimondi S. Guglielmi F. Giorgetti S. Gaetano S.D. Arciello A. Monti D.M. Relini A. Nichino D. Doglia S.M. Natalello A. Pucci P. Mangione P. Obici L. Merlini G. Stoppini M. Robustelli P. Tartaglia G.G. Vendruscolo M. Dobson C.M. Piccoli R. Bellotti V. J. Mol. Biol. 2011; 407: 465-476Crossref PubMed Scopus (42) Google Scholar), suggesting that it is a property of unfolded or non-native proteins. 2) Hydrophobicity is a dominant factor determining the amyloidogenicity of proteins. Because the cross-β structure with a hydrogen bond network is essential for the fibrils (11Nelson R. Eisenberg D. Adv. Protein Chem. 2006; 73: 235-282Crossref PubMed Scopus (178) Google Scholar), the propensity of side chains as well as the main chains to form hydrogen bonds is also important. 3) Alcohols, particularly 2,2,2-trifluoroethanol (TFE) 3The abbreviations used are: TFE2,2,2-trifluoroethanolHFIP1,1,1,3,3,3-hexafluoroisopropanolCMCcritical micelle concentrationhIAPPhuman islet amyloid polypeptideThTthioflavin TAFMatomic force microscopyTEMtransmission electron microscopyTIRFMtotal internal reflection fluorescence microscopy. (12Anderson V.L. Ramlall T.F. Rospigliosi C.C. Webb W.W. Eliezer D. Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 18850-18855Crossref PubMed Scopus (142) Google Scholar) or 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) (13Yamaguchi K. Naiki H. Goto Y. J. Mol. Biol. 2006; 363: 279-288Crossref PubMed Scopus (95) Google Scholar), are useful as cosolvents to induce fibrils. Interestingly, amyloidogenicity is enhanced only at moderate concentrations of alcohols. This is also true of detergents like SDS, for which a concentration close to the critical micelle concentration (CMC) is effective (13Yamaguchi K. Naiki H. Goto Y. J. Mol. Biol. 2006; 363: 279-288Crossref PubMed Scopus (95) Google Scholar, 14Ahmad M.F. Ramakrishna T. Raman B. Rao Ch.M. J. Mol. Biol. 2006; 364: 1061-1072Crossref PubMed Scopus (65) Google Scholar, 15Giehm L. Oliveira C.L. Christiansen G. Pedersen J.S. Otzen D.E. J. Mol. Biol. 2010; 401: 115-133Crossref PubMed Scopus (162) Google Scholar). We suggested that the effects of SDS can be interpreted similarly to those of alcohols (13Yamaguchi K. Naiki H. Goto Y. J. Mol. Biol. 2006; 363: 279-288Crossref PubMed Scopus (95) Google Scholar). 4) One of the most important aspects of amyloidogenicity not focused on so far is that fibrils are common to shorter peptides but rare for proteins of more than 200 amino acids. As far as we know, no case was reported where an entire region of a molecule of more than 20,000 formed fibrils (16Fändrich M. Fletcher M.A. Dobson C.M. Nature. 2001; 410: 165-166Crossref PubMed Scopus (725) Google Scholar, 17Fändrich M. Forge V. Buder K. Kittler M. Dobson C.M. Diekmann S. Proc. Natl. Acad. Sci. U.S.A. 2003; 100: 15463-15468Crossref PubMed Scopus (262) Google Scholar). On the other hand, short fragments tend to exhibit stronger amyloidogenicity than the original proteins (18Kozhukh G.V. Hagihara Y. Kawakami T. Hasegawa K. Naiki H. Goto Y. J. Biol. Chem. 2002; 277: 1310-1315Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). For an example, medin, a 50-residue-long peptide produced from lactadherin, a 364-residue glycoprotein, is a main component of aortic medical amyloid (19Häggqvist B. Näslund J. Sletten K. Westermark G.T. Mucchiano G. Tjernberg L.O. Nordstedt C. Engström U. Westermark P. Proc. Natl. Acad. Sci. U.S.A. 1999; 96: 8669-8674Crossref PubMed Scopus (173) Google Scholar). It is worth noting that various peptide hormones easily form fibrils. Short amyloidogenic peptides form microcrystals useful for obtaining structural insights into amyloid fibrils (11Nelson R. Eisenberg D. Adv. Protein Chem. 2006; 73: 235-282Crossref PubMed Scopus (178) Google Scholar, 20Nelson R. Sawaya M.R. Balbirnie M. Madsen A.Ø. Riekel C. Grothe R. Eisenberg D. Nature. 2005; 435: 773-778Crossref PubMed Scopus (1795) Google Scholar, 21Sawaya M.R. Sambashivan S. Nelson R. Ivanova M.I. Sievers S.A. Apostol M.I. Thompson M.J. Balbirnie M. Wiltzius J.J. McFarlane H.T. Madsen A.Ø. Riekel C. Eisenberg D. Nature. 2007; 447: 453-457Crossref PubMed Scopus (1782) Google Scholar). Taking these findings together, one should consider the formation of amyloid fibrils with respect to the solubility of proteins and peptides in a denatured state. Vendruscolo and co-workers (22Tartaglia G.G. Pechmann S. Dobson C.M. Vendruscolo M. J. Mol. Biol. 2009; 388: 381-389Crossref PubMed Scopus (45) Google Scholar, 23Pechmann S. Vendruscolo M. Mol. Biosyst. 2010; 6: 2490-2497Crossref PubMed Scopus (8) Google Scholar) studied this issue by simulating the competition between folding and aggregation and the solubility of proteins. At the same time, one should consider the difference between amyloid fibrils and amorphous aggregates. To address these issues, it would be useful to examine the effects of alcohols.The effects of alcohols on proteins and peptides have been investigated extensively, including the destruction of the native conformation, the induction of α-helices, and the dissolution of peptide aggregates (24Buck M. Q. Rev. Biophys. 1998; 31: 297-355Crossref PubMed Scopus (709) Google Scholar). These effects can be explained by the polarity of the solvent (24Buck M. Q. Rev. Biophys. 1998; 31: 297-355Crossref PubMed Scopus (709) Google Scholar). In solvents of low polarity, the hydrophobic interactions stabilizing the native structure or peptide aggregates are weakened, and simultaneously local hydrogen bonds are strengthened, resulting in denaturation and the stabilization of extended α-helical structures. Among various alcohols, TFE and HFIP are often used because of their marked potential (25Hirota N. Mizuno K. Goto Y. J. Mol. Biol. 1998; 275: 365-378Crossref PubMed Scopus (226) Google Scholar). This efficiency is linked with the propensity of these alcohols to form dynamic clusters via hydrophobic interactions (26Hong D.P. Hoshino M. Kuboi R. Goto Y. J. Am. Chem. Soc. 1999; 121: 8427-8433Crossref Scopus (354) Google Scholar). The effects of detergents such as SDS can be interpreted in a similar way, in which the formation of micelles is important to understand their effects (13Yamaguchi K. Naiki H. Goto Y. J. Mol. Biol. 2006; 363: 279-288Crossref PubMed Scopus (95) Google Scholar).To examine the effects of alcohols on amyloidogenic proteins in detail, we used human islet amyloid polypeptide (hIAPP, also known as amylin) with a high propensity to form amorphous aggregates as well as amyloid fibrils. hIAPP is a 37-residue peptide hormone with an amidated C terminus and an intramolecular disulfide bond between Cys-2 and Cys-7 (supplemental Fig. S1A). Amyloid fibrils of hIAPP deposit near pancreatic β-cells of type II diabetes, with their presence strongly correlating with a loss of β-cell mass and decreased pancreatic function (27Clark A. Cooper G.J. Lewis C.E. Morris J.F. Willis A.C. Reid K.B. Turner R.C. Lancet. 1987; 2: 231-234Abstract PubMed Scopus (319) Google Scholar, 28Cooper G.J. Willis A.C. Clark A. Turner R.C. Sim R.B. Reid K.B. Proc. Natl. Acad. Sci. U.S.A. 1987; 84: 8628-8632Crossref PubMed Scopus (1161) Google Scholar, 29Westermark P. Wernstedt C. Wilander E. Hayden D.W. O'Brien T.D. Johnson K.H. Proc. Natl. Acad. Sci. U.S.A. 1987; 84: 3881-3885Crossref PubMed Scopus (869) Google Scholar, 30Kahn S.E. Andrikopoulos S. Verchere C.B. Diabetes. 1999; 48: 241-253Crossref PubMed Scopus (424) Google Scholar, 31Marzban L. Park K. Verchere C.B. Exp. Gerontol. 2003; 38: 347-351Crossref PubMed Scopus (148) Google Scholar, 32Hull R.L. Westermark G.T. Westermark P. Kahn S.E. J. Clin. Endocrinol. Metab. 2004; 89: 3629-3643Crossref PubMed Scopus (425) Google Scholar). Soluble hIAPP adopts a predominantly random coil structure, suggesting that it is intrinsically unfolded. Recent structural studies point toward its interaction with membranes (33Engel M.F. Khemtémourian L. Kleijer C.C. Meeldijk H.J. Jacobs J. Verkleij A.J. de Kruijff B. Killian J.A. Höppener J.W. Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 6033-6038Crossref PubMed Scopus (372) Google Scholar, 34Hebda J.A. Miranker A.D. Annu. Rev. Biophys. 2009; 38: 125-152Crossref PubMed Scopus (190) Google Scholar) and an α-helical structure on membranes (12Anderson V.L. Ramlall T.F. Rospigliosi C.C. Webb W.W. Eliezer D. Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 18850-18855Crossref PubMed Scopus (142) Google Scholar, 34Hebda J.A. Miranker A.D. Annu. Rev. Biophys. 2009; 38: 125-152Crossref PubMed Scopus (190) Google Scholar, 35Abedini A. Raleigh D.P. Phys. Biol. 2009; 6: 15005Crossref PubMed Scopus (156) Google Scholar), suggesting the helical intermediate to be on the pathway to the formation of fibrils.In this study, we examined the formation of fibrils by hIAPP in the presence of various concentrations of HFIP using CD, thioflavin T (ThT) fluorescence, atomic force microscopy (AFM), and total internal reflection fluorescence microscopy (TIRFM) (36Ban T. Hamada D. Hasegawa K. Naiki H. Goto Y. J. Biol. Chem. 2003; 278: 16462-16465Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar, 37Ban T. Hoshino M. Takahashi S. Hamada D. Hasegawa K. Naiki H. Goto Y. J. Mol. Biol. 2004; 344: 757-767Crossref PubMed Scopus (206) Google Scholar, 38Ban T. Morigaki K. Yagi H. Kawasaki T. Kobayashi A. Yuba S. Naiki H. Goto Y. J. Biol. Chem. 2006; 281: 33677-33683Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 39Ban T. Yamaguchi K. Goto Y. Acc. Chem. Res. 2006; 39: 663-670Crossref PubMed Scopus (114) Google Scholar). We revealed that moderate concentrations of HFIP at either low or neutral pH efficiently induced the formation of hIAPP fibrils. In the absence of HFIP at neutral pH, hIAPP tended to form amorphous aggregates, suggesting that HFIP destabilizes a pathway leading to these aggregates and instead stabilizes the pathway to the fibrils. Here, we propose that the amyloid fibril is a unique conformation of proteins of relatively short length and peptides when they are excluded from water.CONCLUSIONIn conclusion, the formation of fibrils by hIAPP in the presence of various concentrations of HFIP suggests that amyloid fibrils are one type of protein precipitate formed upon exclusion from an aqueous environment. Amyloid fibrils are distinct from amorphous aggregates in terms of the organized formation of hydrophobic interactions and hydrogen bonds, which is promoted in the presence of moderate concentrations of HFIP. The effects of moderate concentrations of HFIP or SDS may mimic the membrane environment, accelerating the formation of fibrils. We also suggest that the length of the polypeptide chain is critical in determining the morphology of the precipitates of polypeptides, from single crystals to amyloid fibrils and amorphous aggregates. IntroductionAmyloid fibrils play an important role in a range of diseases, including Alzheimer's disease, dialysis-related amyloidosis, and type II diabetes mellitus (1Sipe J.D. Crit. Rev. Clin. Lab. Sci. 1994; 31: 325-354Crossref PubMed Scopus (189) Google Scholar, 2Dobson C.M. Nature. 2003; 426: 884-890Crossref PubMed Scopus (3701) Google Scholar, 3Selkoe D.J. Nat. Cell Biol. 2004; 6: 1054-1061Crossref PubMed Scopus (700) Google Scholar, 4Yamamoto S. Gejyo F. Biochim. Biophys. Acta. 2005; 1753: 4-10Crossref PubMed Scopus (70) Google Scholar). In addition, various proteins and peptides not related to amyloidosis form similar fibrillar deposits in vitro (5Chiti F. Dobson C.M. Annu. Rev. Biochem. 2006; 75: 333-366Crossref PubMed Scopus (5041) Google Scholar). In several cases, the fibrillar deposits are functional (6Fowler D.M. Koulov A.V. Balch W.E. Kelly J.W. Trends Biochem. Sci. 2007; 32: 217-224Abstract Full Text Full Text PDF PubMed Scopus (824) Google Scholar, 7Maji S.K. Perrin M.H. Sawaya M.R. Jessberger S. Vadodaria K. Rissman R.A. Singru P.S. Nilsson K.P. Simon R. Schubert D. Eisenberg D. Rivier J. Sawchenko P. Vale W. Riek R. Science. 2009; 325: 328-332Crossref PubMed Scopus (750) Google Scholar). Although the biological impact of amyloid fibrils is tremendous, we still do not have a general view of why and how the fibrils form. On the other hand, we have increasing evidence suggesting the underlying mechanism of fibril formation. 1) First, fibril formation is coupled with the denaturation of proteins (8Kelly J.W. Curr. Opin. Struct. Biol. 1998; 8: 101-106Crossref PubMed Scopus (946) Google Scholar, 9Khurana R. Gillespie J.R. Talapatra A. Minert L.J. Ionescu-Zanetti C. Millett I. Fink A.L. Biochemistry. 2001; 40: 3525-3535Crossref PubMed Scopus (288) Google Scholar, 10Raimondi S. Guglielmi F. Giorgetti S. Gaetano S.D. Arciello A. Monti D.M. Relini A. Nichino D. Doglia S.M. Natalello A. Pucci P. Mangione P. Obici L. Merlini G. Stoppini M. Robustelli P. Tartaglia G.G. Vendruscolo M. Dobson C.M. Piccoli R. Bellotti V. J. Mol. Biol. 2011; 407: 465-476Crossref PubMed Scopus (42) Google Scholar), suggesting that it is a property of unfolded or non-native proteins. 2) Hydrophobicity is a dominant factor determining the amyloidogenicity of proteins. Because the cross-β structure with a hydrogen bond network is essential for the fibrils (11Nelson R. Eisenberg D. Adv. Protein Chem. 2006; 73: 235-282Crossref PubMed Scopus (178) Google Scholar), the propensity of side chains as well as the main chains to form hydrogen bonds is also important. 3) Alcohols, particularly 2,2,2-trifluoroethanol (TFE) 3The abbreviations used are: TFE2,2,2-trifluoroethanolHFIP1,1,1,3,3,3-hexafluoroisopropanolCMCcritical micelle concentrationhIAPPhuman islet amyloid polypeptideThTthioflavin TAFMatomic force microscopyTEMtransmission electron microscopyTIRFMtotal internal reflection fluorescence microscopy. (12Anderson V.L. Ramlall T.F. Rospigliosi C.C. Webb W.W. Eliezer D. Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 18850-18855Crossref PubMed Scopus (142) Google Scholar) or 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) (13Yamaguchi K. Naiki H. Goto Y. J. Mol. Biol. 2006; 363: 279-288Crossref PubMed Scopus (95) Google Scholar), are useful as cosolvents to induce fibrils. Interestingly, amyloidogenicity is enhanced only at moderate concentrations of alcohols. This is also true of detergents like SDS, for which a concentration close to the critical micelle concentration (CMC) is effective (13Yamaguchi K. Naiki H. Goto Y. J. Mol. Biol. 2006; 363: 279-288Crossref PubMed Scopus (95) Google Scholar, 14Ahmad M.F. Ramakrishna T. Raman B. Rao Ch.M. J. Mol. Biol. 2006; 364: 1061-1072Crossref PubMed Scopus (65) Google Scholar, 15Giehm L. Oliveira C.L. Christiansen G. Pedersen J.S. Otzen D.E. J. Mol. Biol. 2010; 401: 115-133Crossref PubMed Scopus (162) Google Scholar). We suggested that the effects of SDS can be interpreted similarly to those of alcohols (13Yamaguchi K. Naiki H. Goto Y. J. Mol. Biol. 2006; 363: 279-288Crossref PubMed Scopus (95) Google Scholar). 4) One of the most important aspects of amyloidogenicity not focused on so far is that fibrils are common to shorter peptides but rare for proteins of more than 200 amino acids. As far as we know, no case was reported where an entire region of a molecule of more than 20,000 formed fibrils (16Fändrich M. Fletcher M.A. Dobson C.M. Nature. 2001; 410: 165-166Crossref PubMed Scopus (725) Google Scholar, 17Fändrich M. Forge V. Buder K. Kittler M. Dobson C.M. Diekmann S. Proc. Natl. Acad. Sci. U.S.A. 2003; 100: 15463-15468Crossref PubMed Scopus (262) Google Scholar). On the other hand, short fragments tend to exhibit stronger amyloidogenicity than the original proteins (18Kozhukh G.V. Hagihara Y. Kawakami T. Hasegawa K. Naiki H. Goto Y. J. Biol. Chem. 2002; 277: 1310-1315Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). For an example, medin, a 50-residue-long peptide produced from lactadherin, a 364-residue glycoprotein, is a main component of aortic medical amyloid (19Häggqvist B. Näslund J. Sletten K. Westermark G.T. Mucchiano G. Tjernberg L.O. Nordstedt C. Engström U. Westermark P. Proc. Natl. Acad. Sci. U.S.A. 1999; 96: 8669-8674Crossref PubMed Scopus (173) Google Scholar). It is worth noting that various peptide hormones easily form fibrils. Short amyloidogenic peptides form microcrystals useful for obtaining structural insights into amyloid fibrils (11Nelson R. Eisenberg D. Adv. Protein Chem. 2006; 73: 235-282Crossref PubMed Scopus (178) Google Scholar, 20Nelson R. Sawaya M.R. Balbirnie M. Madsen A.Ø. Riekel C. Grothe R. Eisenberg D. Nature. 2005; 435: 773-778Crossref PubMed Scopus (1795) Google Scholar, 21Sawaya M.R. Sambashivan S. Nelson R. Ivanova M.I. Sievers S.A. Apostol M.I. Thompson M.J. Balbirnie M. Wiltzius J.J. McFarlane H.T. Madsen A.Ø. Riekel C. Eisenberg D. Nature. 2007; 447: 453-457Crossref PubMed Scopus (1782) Google Scholar). Taking these findings together, one should consider the formation of amyloid fibrils with respect to the solubility of proteins and peptides in a denatured state. Vendruscolo and co-workers (22Tartaglia G.G. Pechmann S. Dobson C.M. Vendruscolo M. J. Mol. Biol. 2009; 388: 381-389Crossref PubMed Scopus (45) Google Scholar, 23Pechmann S. Vendruscolo M. Mol. Biosyst. 2010; 6: 2490-2497Crossref PubMed Scopus (8) Google Scholar) studied this issue by simulating the competition between folding and aggregation and the solubility of proteins. At the same time, one should consider the difference between amyloid fibrils and amorphous aggregates. To address these issues, it would be useful to examine the effects of alcohols.The effects of alcohols on proteins and peptides have been investigated extensively, including the destruction of the native conformation, the induction of α-helices, and the dissolution of peptide aggregates (24Buck M. Q. Rev. Biophys. 1998; 31: 297-355Crossref PubMed Scopus (709) Google Scholar). These effects can be explained by the polarity of the solvent (24Buck M. Q. Rev. Biophys. 1998; 31: 297-355Crossref PubMed Scopus (709) Google Scholar). In solvents of low polarity, the hydrophobic interactions stabilizing the native structure or peptide aggregates are weakened, and simultaneously local hydrogen bonds are strengthened, resulting in denaturation and the stabilization of extended α-helical structures. Among various alcohols, TFE and HFIP are often used because of their marked potential (25Hirota N. Mizuno K. Goto Y. J. Mol. Biol. 1998; 275: 365-378Crossref PubMed Scopus (226) Google Scholar). This efficiency is linked with the propensity of these alcohols to form dynamic clusters via hydrophobic interactions (26Hong D.P. Hoshino M. Kuboi R. Goto Y. J. Am. Chem. Soc. 1999; 121: 8427-8433Crossref Scopus (354) Google Scholar). The effects of detergents such as SDS can be interpreted in a similar way, in which the formation of micelles is important to understand their effects (13Yamaguchi K. Naiki H. Goto Y. J. Mol. Biol. 2006; 363: 279-288Crossref PubMed Scopus (95) Google Scholar).To examine the effects of alcohols on amyloidogenic proteins in detail, we used human islet amyloid polypeptide (hIAPP, also known as amylin) with a high propensity to form amorphous aggregates as well as amyloid fibrils. hIAPP is a 37-residue peptide hormone with an amidated C terminus and an intramolecular disulfide bond between Cys-2 and Cys-7 (supplemental Fig. S1A). Amyloid fibrils of hIAPP deposit near pancreatic β-cells of type II diabetes, with their presence strongly correlating with a loss of β-cell mass and decreased pancreatic function (27Clark A. Cooper G.J. Lewis C.E. Morris J.F. Willis A.C. Reid K.B. Turner R.C. Lancet. 1987; 2: 231-234Abstract PubMed Scopus (319) Google Scholar, 28Cooper G.J. Willis A.C. Clark A. Turner R.C. Sim R.B. Reid K.B. Proc. Natl. Acad. Sci. U.S.A. 1987; 84: 8628-8632Crossref PubMed Scopus (1161) Google Scholar, 29Westermark P. Wernstedt C. Wilander E. Hayden D.W. O'Brien T.D. Johnson K.H. Proc. Natl. Acad. Sci. U.S.A. 1987; 84: 3881-3885Crossref PubMed Scopus (869) Google Scholar, 30Kahn S.E. Andrikopoulos S. Verchere C.B. Diabetes. 1999; 48: 241-253Crossref PubMed Scopus (424) Google Scholar, 31Marzban L. Park K. Verchere C.B. Exp. Gerontol. 2003; 38: 347-351Crossref PubMed Scopus (148) Google Scholar, 32Hull R.L. Westermark G.T. Westermark P. Kahn S.E. J. Clin. Endocrinol. Metab. 2004; 89: 3629-3643Crossref PubMed Scopus (425) Google Scholar). Soluble hIAPP adopts a predominantly random coil structure, suggesting that it is intrinsically unfolded. Recent structural studies point toward its interaction with membranes (33Engel M.F. Khemtémourian L. Kleijer C.C. Meeldijk H.J. Jacobs J. Verkleij A.J. de Kruijff B. Killian J.A. Höppener J.W. Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 6033-6038Crossref PubMed Scopus (372) Google Scholar, 34Hebda J.A. Miranker A.D. Annu. Rev. Biophys. 2009; 38: 125-152Crossref PubMed Scopus (190) Google Scholar) and an α-helical structure on membranes (12Anderson V.L. Ramlall T.F. Rospigliosi C.C. Webb W.W. Eliezer D. Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 18850-18855Crossref PubMed Scopus (142) Google Scholar, 34Hebda J.A. Miranker A.D. Annu. Rev. Biophys. 2009; 38: 125-152Crossref PubMed Scopus (190) Google Scholar, 35Abedini A. Raleigh D.P. Phys. Biol. 2009; 6: 15005Crossref PubMed Scopus (156) Google Scholar), suggesting the helical intermediate to be on the pathway to the formation of fibrils.In this study, we examined the formation of fibrils by hIAPP in the presence of various concentrations of HFIP using CD, thioflavin T (ThT) fluorescence, atomic force microscopy (AFM), and total internal reflection fluorescence microscopy (TIRFM) (36Ban T. Hamada D. Hasegawa K. Naiki H. Goto Y. J. Biol. Chem. 2003; 278: 16462-16465Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar, 37Ban T. Hoshino M. Takahashi S. Hamada D. Hasegawa K. Naiki H. Goto Y. J. Mol. Biol. 2004; 344: 757-767Crossref PubMed Scopus (206) Google Scholar, 38Ban T. Morigaki K. Yagi H. Kawasaki T. Kobayashi A. Yuba S. Naiki H. Goto Y. J. Biol. Chem. 2006; 281: 33677-33683Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 39Ban T. Yamaguchi K. Goto Y. Acc. Chem. Res. 2006; 39: 663-670Crossref PubMed Scopus (114) Google Scholar). We revealed that moderate concentrations of HFIP at either low or neutral pH efficiently induced the formation of hIAPP fibrils. In the absence of HFIP at neutral pH, hIAPP tended to form amorphous aggregates, suggesting that HFIP destabilizes a pathway leading to these aggregates and instead stabilizes the pathway to the fibrils. Here, we propose that the amyloid fibril is a unique conformation of proteins of relatively short length and peptides when they are excluded from water." @default.
• W1994560730 created "2016-06-24" @default.
• W1994560730 creator A5005740050 @default.
• W1994560730 creator A5019218504 @default.
• W1994560730 creator A5022600763 @default.
• W1994560730 creator A5032879623 @default.
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• W1994560730 creator A5072685957 @default.
• W1994560730 date "2011-07-01" @default.
• W1994560730 modified "2023-10-16" @default.
• W1994560730 title "Hexafluoroisopropanol Induces Amyloid Fibrils of Islet Amyloid Polypeptide by Enhancing Both Hydrophobic and Electrostatic Interactions" @default.
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• W1994560730 doi "https://doi.org/10.1074/jbc.m111.226688" @default.
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