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• W2134262589 abstract "Islet amyloid polypeptide (IAPP) is a 37-amino acid amyloid protein intimately associated with pancreatic islet β-cell dysfunction and death in type II diabetes. In this study, we combine spectroscopic methods and microscopy to investigate α-helical IAPP-membrane interactions. Using light scattering and fluorescence microscopy, we observe that larger vesicles become smaller upon treatment with human or rat IAPP. Electron microscopy shows the formation of various highly curved structures such as tubules or smaller vesicles in a membrane-remodeling process, and spectrofluorometric detection of vesicle leakage shows disruption of membrane integrity. This effect is stronger for human IAPP than for the less toxic rat IAPP. From CD spectra in the presence of different-sized vesicles, we also uncover the membrane curvature-sensing ability of IAPP and find that it transitions from inducing to sensing membrane curvature when lipid negative charge is decreased. Our in vivo EM images of immunogold-labeled rat IAPP and human IAPP show both forms to localize to mitochondrial cristae, which contain not only locally curved membranes but also phosphatidylethanolamine and cardiolipin, lipids with high spontaneous negative curvature. Disruption of membrane integrity by induction of membrane curvature could apply more broadly to other amyloid proteins and be responsible for membrane damage observed in other amyloid diseases as well. Islet amyloid polypeptide (IAPP) is a 37-amino acid amyloid protein intimately associated with pancreatic islet β-cell dysfunction and death in type II diabetes. In this study, we combine spectroscopic methods and microscopy to investigate α-helical IAPP-membrane interactions. Using light scattering and fluorescence microscopy, we observe that larger vesicles become smaller upon treatment with human or rat IAPP. Electron microscopy shows the formation of various highly curved structures such as tubules or smaller vesicles in a membrane-remodeling process, and spectrofluorometric detection of vesicle leakage shows disruption of membrane integrity. This effect is stronger for human IAPP than for the less toxic rat IAPP. From CD spectra in the presence of different-sized vesicles, we also uncover the membrane curvature-sensing ability of IAPP and find that it transitions from inducing to sensing membrane curvature when lipid negative charge is decreased. Our in vivo EM images of immunogold-labeled rat IAPP and human IAPP show both forms to localize to mitochondrial cristae, which contain not only locally curved membranes but also phosphatidylethanolamine and cardiolipin, lipids with high spontaneous negative curvature. Disruption of membrane integrity by induction of membrane curvature could apply more broadly to other amyloid proteins and be responsible for membrane damage observed in other amyloid diseases as well. Many neurodegenerative diseases, such as Alzheimer, Parkinson, and Huntington diseases, and type II diabetes are associated with amyloidogenic proteins (1Glabe C.G. Common mechanisms of amyloid oligomer pathogenesis in degenerative disease.Neurobiol. Aging. 2006; 27: 570-575Crossref PubMed Scopus (469) Google Scholar). Islet amyloid polypeptide (IAPP 4The abbreviations used are: IAPPislet amyloid polypeptidehIAPPhuman IAPPrIAPPrat IAPPThTthioflavin TMLVmultilamellar vesiclePOPS1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-l-serine]POPG1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-RAC-(1-glycerol)]DOPG1,2-dioleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)]HFIPhexafluoroisopropanolANTS8-aminonaphthalene-1,3,6-trisulfonic acidDPXp-xylene-bis(pyridinium bromide)Rh-PE1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[lissamine rhodamine B sulfonyl]POPC1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholineLUVlarge unilamellar vesicleSUVsmall unilamellar vesicleNBD-PS1-palmitoyl-2-{12-[(7-nitro-2–1,3-benzoxadiazol-4-yl)amino]dodecanoyl}-sn-glycero-3-phosphoserinebiotin-PE1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(cap biotinyl)GUVgiant unilamellar vesicleMREmean residue ellipticity. or amylin), a 37-residue peptide co-secreted with insulin (2Butler P.C. Chou J. Carter W.B. Wang Y.N. Bu B.H. Chang D. Chang J.K. Rizza R.A. Effects of meal ingestion on plasma amylin concentration in NIDDM and nondiabetic humans.Diabetes. 1990; 39: 752-756Crossref PubMed Scopus (302) Google Scholar, 3Woods S.C. Lutz T.A. Geary N. Langhans W. Pancreatic signals controlling food intake; insulin, glucagon and amylin.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2006; 361: 1219-1235Crossref PubMed Scopus (191) Google Scholar), is the principal component of islet amyloid commonly present in type II diabetes (4Cooper G.J. Willis A.C. Clark A. Turner R.C. Sim R.B. Reid K.B. Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients.Proc. Natl. Acad. Sci. U.S.A. 1987; 84: 8628-8632Crossref PubMed Scopus (1173) Google Scholar). Furthermore, numerous cell and animal studies support a causative role of human IAPP (hIAPP) in type II diabetes (5Janson J. Soeller W.C. Roche P.C. Nelson R.T. Torchia A.J. Kreutter D.K. Butler P.C. Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide.Proc. Natl. Acad. Sci. U.S.A. 1996; 93: 7283-7288Crossref PubMed Scopus (302) Google Scholar, 6Gurlo T. Ryazantsev S. Huang C.J. Yeh M.W. Reber H.A. Hines O.J. O'Brien T.D. Glabe C.G. Butler P.C. Evidence for proteotoxicity in beta cells in type 2 diabetes: toxic islet amyloid polypeptide oligomers form intracellularly in the secretory pathway.Am. J. Pathol. 2010; 176: 861-869Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 7Zhang S. Liu H. Chuang C.L. Li X. Au M. Zhang L. Phillips A.R. Scott D.W. Cooper G.J. The pathogenic mechanism of diabetes varies with the degree of overexpression and oligomerization of human amylin in the pancreatic islet beta cells.FASEB J. 2014; 28: 5083-5096Crossref PubMed Scopus (35) Google Scholar). As in the case of other amyloidogenic proteins (8Burke K.A. Hensal K.M. Umbaugh C.S. Chaibva M. Legleiter J. Huntingtin disrupts lipid bilayers in a polyQ-length dependent manner.Biochim. Biophys. Acta. 2013; 1828: 1953-1961Crossref PubMed Scopus (50) Google Scholar, 9Thapa A. Vernon B.C. De la Peña K. Soliz G. Moreno H.A. López G.P. Chi E.Y. Membrane-mediated neuroprotection by curcumin from amyloid-β-peptide-induced toxicity.Langmuir. 2013; 29: 11713-11723Crossref PubMed Scopus (48) Google Scholar, 10Stefanovic A.N. Stöckl M.T. Claessens M.M. Subramaniam V. α-Synuclein oligomers distinctively permeabilize complex model membranes.FEBS J. 2014; 281: 2838-2850Crossref PubMed Scopus (47) Google Scholar), disruption of membrane integrity is thought to be one of the mechanisms by which IAPP can cause toxicity (5Janson J. Soeller W.C. Roche P.C. Nelson R.T. Torchia A.J. Kreutter D.K. Butler P.C. Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide.Proc. Natl. Acad. Sci. U.S.A. 1996; 93: 7283-7288Crossref PubMed Scopus (302) Google Scholar, 11Janson J. Ashley R.H. Harrison D. McIntyre S. Butler P.C. The mechanism of islet amyloid polypeptide toxicity is membrane disruption by intermediate-sized toxic amyloid particles.Diabetes. 1999; 48: 491-498Crossref PubMed Scopus (513) Google Scholar, 12Magzoub M. Miranker A.D. Concentration-dependent transitions govern the subcellular localization of islet amyloid polypeptide.FASEB J. 2012; 26: 1228-1238Crossref PubMed Scopus (71) Google Scholar). islet amyloid polypeptide human IAPP rat IAPP thioflavin T multilamellar vesicle 1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-l-serine] 1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-RAC-(1-glycerol)] 1,2-dioleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] hexafluoroisopropanol 8-aminonaphthalene-1,3,6-trisulfonic acid p-xylene-bis(pyridinium bromide) 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[lissamine rhodamine B sulfonyl] 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine large unilamellar vesicle small unilamellar vesicle 1-palmitoyl-2-{12-[(7-nitro-2–1,3-benzoxadiazol-4-yl)amino]dodecanoyl}-sn-glycero-3-phosphoserine 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(cap biotinyl) giant unilamellar vesicle mean residue ellipticity. Different mechanisms have been proposed for IAPP-dependent membrane damage, with some of the more recent studies (13Brender J.R. Lee E.L. Cavitt M.A. Gafni A. Steel D.G. Ramamoorthy A. Amyloid fiber formation and membrane disruption are separate processes localized in two distinct regions of IAPP, the type-2-diabetes-related peptide.J. Am. Chem. Soc. 2008; 130: 6424-6429Crossref PubMed Scopus (198) Google Scholar, 14Brender J.R. Lee E.L. Hartman K. Wong P.T. Ramamoorthy A. Steel D.G. Gafni A. Biphasic effects of insulin on islet amyloid polypeptide membrane disruption.Biophys. J. 2011; 100: 685-692Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 15Heyl D.L. Osborne J.M. Pamarthy S. Samisetti S. Gray A.W. Jayaprakash A. Konda S. Brown D.J. Miller S.R. Eizadkhah R. Milletti M.C. Liposome damage and modeling of fragments of human islet amyloid polypeptide (IAPP) support a two-step model of membrane destruction.Int. J. Pept. Res. Ther. 2010; 16: 43-54Crossref Scopus (9) Google Scholar) illustrating IAPP-mediated membrane disruption to occur in two or possibly more (16Last N.B. Rhoades E. Miranker A.D. Islet amyloid polypeptide demonstrates a persistent capacity to disrupt membrane integrity.Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 9460-9465Crossref PubMed Scopus (112) Google Scholar) steps. In one model, hIAPP damages membranes at the amyloid fibril formation stage, such that hIAPP fibrils forming near the membrane extract lipid from the membrane as they grow; this lipid uptake process results in nonspecific rupturing and fragmentation of the membrane by the nascent fibrils (17Sparr E. Engel M.F. Sakharov D.V. Sprong M. Jacobs J. de Kruijff B. Höppener J.W. Killian J.A. Islet amyloid polypeptide-induced membrane leakage involves uptake of lipids by forming amyloid fibers.FEBS Lett. 2004; 577: 117-120Crossref PubMed Scopus (220) Google Scholar, 18Engel M.F. Khemtémourian L. Kleijer C.C. Meeldijk H.J. Jacobs J. Verkleij A.J. de Kruijff B. Killian J.A. Höppener J.W. Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane.Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 6033-6038Crossref PubMed Scopus (373) Google Scholar). However, rat IAPP (rIAPP), which does not readily form fibrils (19Westermark P. Engström U. Johnson K.H. Westermark G.T. Betsholtz C. Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation.Proc. Natl. Acad. Sci. U.S.A. 1990; 87: 5036-5040Crossref PubMed Scopus (705) Google Scholar), has also been seen to cause membrane leakage in vitro (16Last N.B. Rhoades E. Miranker A.D. Islet amyloid polypeptide demonstrates a persistent capacity to disrupt membrane integrity.Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 9460-9465Crossref PubMed Scopus (112) Google Scholar) and confer some (albeit strongly reduced) cytotoxicity in vivo (12Magzoub M. Miranker A.D. Concentration-dependent transitions govern the subcellular localization of islet amyloid polypeptide.FASEB J. 2012; 26: 1228-1238Crossref PubMed Scopus (71) Google Scholar). Also, the nonamyloidogenic hIAPP(1–19) fragment as well as a number of nonamyloidogenic full-length variants of IAPP have been observed to cause leakage of synthetic membranes (13Brender J.R. Lee E.L. Cavitt M.A. Gafni A. Steel D.G. Ramamoorthy A. Amyloid fiber formation and membrane disruption are separate processes localized in two distinct regions of IAPP, the type-2-diabetes-related peptide.J. Am. Chem. Soc. 2008; 130: 6424-6429Crossref PubMed Scopus (198) Google Scholar, 15Heyl D.L. Osborne J.M. Pamarthy S. Samisetti S. Gray A.W. Jayaprakash A. Konda S. Brown D.J. Miller S.R. Eizadkhah R. Milletti M.C. Liposome damage and modeling of fragments of human islet amyloid polypeptide (IAPP) support a two-step model of membrane destruction.Int. J. Pept. Res. Ther. 2010; 16: 43-54Crossref Scopus (9) Google Scholar, 20Cao P. Abedini A. Wang H. Tu L.H. Zhang X. Schmidt A.M. Raleigh D.P. Islet amyloid polypeptide toxicity and membrane interactions.Proc. Natl. Acad. Sci. U.S.A. 2013; 110: 19279-19284Crossref PubMed Scopus (113) Google Scholar), and hIAPP(1–19) and rIAPP(1–19) can permeabilize pancreatic islet cell membranes (21Brender J.R. Hartman K. Reid K.R. Kennedy R.T. Ramamoorthy A. A single mutation in the nonamyloidogenic region of islet amyloid polypeptide greatly reduces toxicity.Biochemistry. 2008; 47: 12680-12688Crossref PubMed Scopus (128) Google Scholar). Therefore, fibril growth cannot be the sole mechanism involved. Other mechanisms have been suggested that are analogous to those utilized by antimicrobial peptides (22Shai Y. Mechanism of the binding, insertion and destabilization of phospholipid bilayer membranes by α-helical antimicrobial and cell non-selective membrane-lytic peptides.Biochim. Biophys. Acta. 1999; 1462: 55-70Crossref PubMed Scopus (1574) Google Scholar, 23Jayasinghe S.A. Langen R. Membrane interaction of islet amyloid polypeptide.Biochim. Biophys. Acta. 2007; 1768: 2002-2009Crossref PubMed Scopus (157) Google Scholar, 24Almeida P.F. Pokorny A. Mechanisms of antimicrobial, cytolytic, and cell-penetrating peptides: from kinetics to thermodynamics.Biochemistry. 2009; 48: 8083-8093Crossref PubMed Scopus (225) Google Scholar). Peptides that employ the detergent-like carpet mechanism cause widespread defects throughout the membrane surface in a nonspecific manner (25Gazit E. Miller I.R. Biggin P.C. Sansom M.S. Shai Y. Structure and orientation of the mammalian antibacterial peptide cecropin P1 within phospholipid membranes.J. Mol. Biol. 1996; 258: 860-870Crossref PubMed Scopus (225) Google Scholar, 26Oren Z. Shai Y. Mode of action of linear amphipathic α-helical antimicrobial peptides.Biopolymers. 1998; 47: 451-463Crossref PubMed Scopus (755) Google Scholar, 27Sato H. 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Soc. 2008; 130: 4338-4346Crossref PubMed Scopus (54) Google Scholar) or, alternatively, peptides inducing the membrane to form a toroidal pore lined by its own phospholipids (31Allende D. Simon S.A. McIntosh T.J. Melittin-induced bilayer leakage depends on lipid material properties: evidence for toroidal pores.Biophys. J. 2005; 88: 1828-1837Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar, 32Sengupta D. Leontiadou H. Mark A.E. Marrink S.J. Toroidal pores formed by antimicrobial peptides show significant disorder.Biochim. Biophys. Acta. 2008; 1778: 2308-2317Crossref PubMed Scopus (408) Google Scholar, 33Bertelsen K. Dorosz J. Hansen S.K. Nielsen N.C. Vosegaard T. Mechanisms of peptide-induced pore formation in lipid bilayers investigated by oriented 31P solid-state NMR spectroscopy.PLoS ONE. 2012; 7e47745Crossref PubMed Scopus (38) Google Scholar). Different studies have proposed a variety of mechanisms such as these for IAPP, including pore mechanisms (16Last N.B. Rhoades E. Miranker A.D. Islet amyloid polypeptide demonstrates a persistent capacity to disrupt membrane integrity.Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 9460-9465Crossref PubMed Scopus (112) Google Scholar, 34Green J.D. Kreplak L. Goldsbury C. Li Blatter X. Stolz M. Cooper G.S. Seelig A. Kistler J. Aebi U. Atomic force microscopy reveals defects within mica supported lipid bilayers induced by the amyloidogenic human amylin peptide.J. Mol. Biol. 2004; 342: 877-887Crossref PubMed Scopus (144) Google Scholar, 35Smith P.E. Brender J.R. Ramamoorthy A. Induction of negative curvature as a mechanism of cell toxicity by amyloidogenic peptides: the case of islet amyloid polypeptide.J. Am. Chem. Soc. 2009; 131: 4470-4478Crossref PubMed Scopus (123) Google Scholar, 36Xu W. Wei G. Su H. Nordenskiöld L. Mu Y. Effects of cholesterol on pore formation in lipid bilayers induced by human islet amyloid polypeptide fragments: a coarse-grained molecular dynamics study.Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 2011; 84 (051922)Crossref Scopus (25) Google Scholar, 37Last N.B. Miranker A.D. Common mechanism unites membrane poration by amyloid and antimicrobial peptides.Proc. Natl. Acad. Sci. U.S.A. 2013; 110: 6382-6387Crossref PubMed Scopus (132) Google Scholar, 38Pannuzzo M. Raudino A. Milardi D. La Rosa C. Karttunen M. α-Helical structures drive early stages of self-assembly of amyloidogenic amyloid polypeptide aggregate formation in membranes.Sci. Rep. 2013; 32781Crossref PubMed Scopus (83) Google Scholar). Given the increasingly established bi- or multiphasicity of IAPP-mediated membrane damage (13Brender J.R. Lee E.L. Cavitt M.A. Gafni A. Steel D.G. Ramamoorthy A. Amyloid fiber formation and membrane disruption are separate processes localized in two distinct regions of IAPP, the type-2-diabetes-related peptide.J. Am. Chem. Soc. 2008; 130: 6424-6429Crossref PubMed Scopus (198) Google Scholar, 14Brender J.R. Lee E.L. Hartman K. Wong P.T. Ramamoorthy A. Steel D.G. Gafni A. Biphasic effects of insulin on islet amyloid polypeptide membrane disruption.Biophys. J. 2011; 100: 685-692Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 15Heyl D.L. Osborne J.M. Pamarthy S. Samisetti S. Gray A.W. Jayaprakash A. Konda S. Brown D.J. Miller S.R. Eizadkhah R. Milletti M.C. Liposome damage and modeling of fragments of human islet amyloid polypeptide (IAPP) support a two-step model of membrane destruction.Int. J. Pept. Res. Ther. 2010; 16: 43-54Crossref Scopus (9) Google Scholar, 16Last N.B. Rhoades E. Miranker A.D. Islet amyloid polypeptide demonstrates a persistent capacity to disrupt membrane integrity.Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 9460-9465Crossref PubMed Scopus (112) Google Scholar), one or more of the above mechanisms could be part of an early step, with the later or latest step involving β-sheet fibril formation. One possibility that remains unexplored is that IAPP induces membrane curvature as an α-helical wedge. Prior to forming β-sheet fibrils, IAPP is known to bind to negatively charged lipids and detergents using an amphipathic α-helical structure (39Jayasinghe S.A. Langen R. Lipid membranes modulate the structure of islet amyloid polypeptide.Biochemistry. 2005; 44: 12113-12119Crossref PubMed Scopus (226) Google Scholar, 40Knight J.D. Hebda J.A. Miranker A.D. Conserved and cooperative assembly of membrane-bound α-helical states of islet amyloid polypeptide.Biochemistry. 2006; 45: 9496-9508Crossref PubMed Scopus (269) Google Scholar, 41Apostolidou M. Jayasinghe S.A. Langen R. Structure of α-helical membrane-bound human islet amyloid polypeptide and its implications for membrane-mediated misfolding.J. Biol. Chem. 2008; 283: 17205-17210Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, 42Patil S.M. Xu S. Sheftic S.R. Alexandrescu A.T. Dynamic α-helix structure of micelle-bound human amylin.J. Biol. 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Yang M.A. Terada M. Hu J. Bushong E.A. Hwang M. Masliah E. George J.M. Ellisman M.H. Mapping the subcellular distribution of α-synuclein in neurons using genetically encoded probes for correlated light and electron microscopy: implications for Parkinson's disease pathogenesis.J. Neurosci. 2013; 33: 2605-2615Crossref PubMed Scopus (102) Google Scholar). We therefore tested whether some of the previously observed membrane-disrupting effects of IAPP might have been caused by induction of membrane curvature. Moreover, prior studies on membrane curvature-inducing proteins have shown that such proteins can also exhibit curvature-sensitive membrane binding under some conditions (44Peter B.J. Kent H.M. Mills I.G. Vallis Y. Butler P.J. Evans P.R. McMahon H.T. BAR domains as sensors of membrane curvature: the amphiphysin BAR structure.Science. 2004; 303: 495-499Crossref PubMed Scopus (1348) Google Scholar, 57Bhatia V.K. Madsen K.L. Bolinger P.Y. Kunding A. Hedegård P. Gether U. Stamou D. Amphipathic motifs in BAR domains are essential for membrane curvature sensing.EMBO J. 2009; 28: 3303-3314Crossref PubMed Scopus (201) Google Scholar, 58Madsen K.L. Bhatia V.K. Gether U. Stamou D. BAR domains, amphipathic helices and membrane-anchored proteins use the same mechanism to sense membrane curvature.FEBS Lett. 2010; 584: 1848-1855Crossref PubMed Scopus (72) Google Scholar, 59Cui H. Lyman E. Voth G.A. Mechanism of membrane curvature sensing by amphipathic helix containing proteins.Biophys. J. 2011; 100: 1271-1279Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 60Pranke I.M. Morello V. Bigay J. Gibson K. Verbavatz J.M. Antonny B. Jackson C.L. α-Synuclein and ALPS motifs are membrane curvature sensors whose contrasting chemistry mediates selective vesicle binding.J. Cell Biol. 2011; 194: 89-103Crossref PubMed Scopus (149) Google Scholar, 61Ouberai M.M. Wang J. Swann M.J. Galvagnion C. Guilliams T. Dobson C.M. Welland M.E. α-Synuclein senses lipid packing defects and induces lateral expansion of lipids leading to membrane remodeling.J. Biol. Chem. 2013; 288: 20883-20895Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar). Inasmuch as sensing of membrane curvature could have implications for physiological and pathogenic recruitment of IAPP to membranes, we also investigated the curvature sensitivity of the IAPP-membrane interaction. Using circular dichroism (CD), spectrophotometry, and fluorescence microscopy of GUVs, we find that α-helical IAPP converts large, negatively charged vesicles into much smaller structures. Dye leakage experiments indicate that this membrane remodeling coincides with significant disruption of membrane integrity, and electron microscopy reveals the IAPP-dependent formation of lipid tubules and smaller vesicles. By uncovering IAPP as a curvature inducer, we can correlate the previously discovered early phase of membrane leakage with the modulation of membrane architecture into highly curved structures. When using only weakly negatively charged membranes, we find that IAPP transitions from an inducer of membrane curvature to a sensor of membrane curvature. The induction or sensing of membrane curvature may impact IAPP's physiological and pathological functions and govern its membrane localization in vivo. In support of this notion, we show that IAPP preferentially localizes to mitochondria, where it interacts with cristae. Cristae are curved membrane structures rich in cardiolipin and phosphatidylethanolamine, lipids with pronounced negative spontaneous curvature. Synthetic hIAPP was obtained from Bachem (Torrance, CA), and synthetic rIAPP was from BiomerTech (Pleasanton, CA). 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-l-serine] (POPS), 1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-RAC-(1-glycerol)] (POPG), 1,2-dioleoyl-sn-glycero-3-[phospho-RAC-(1-glycerol)] (DOPG), 1-palmitoyl-2-{12-[(7-nitro-2–1,3-benzoxadiazol-4-yl)amino]dodecanoyl}-sn-glycero-3-phosphoserine (NBD-PS), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[lissamine rhodamine B sulfonyl] (Rh-PE), and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(cap biotinyl) (biotin-PE) were obtained as solutions in chloroform from Avanti Polar Lipids, Inc. (Alabaster, AL). Hexafluoroisopropanol (HFIP), HEPES, thioflavin T (ThT), Triton X-100, and asolectin were obtained from Sigma; 8-aminonaphthalene-1,3,6-trisulfonic acid (ANTS), p-xylene-bis(pyridinium bromide) (DPX), and avidin were from Life Technologies, Inc.; guanidine hydrochloride was from Thermo Scientific; and uranyl acetate was from Electron Microscopy Sciences (EMS, Hatfield, PA). Polydimethylsiloxane was purchased from Dow Corning (Midland, MI). hIAPP or rIAPP powder was initially dissolved in HFIP. To quantify peptide concentrations, a small amount of peptide was isolated; the HFIP was evaporated under a stream of nitrogen gas and replaced with 8 m guanidine HCl, and absorbance at 280 nm was measured. hIAPP in HFIP was then aliquoted, flash-frozen in liquid N2, and lyophilized overnight. Immediately prior to each experiment, hIAPP was redissolved in 10 μl of deionized water containing 0.5% acetic acid, to which 40 μl of 110 mm HEPES, pH 7.4, was added. The resulting peptide solution was added to vesicles to a final peptide concentration of 25 μm (unless otherw" @default.
• W2134262589 created "2016-06-24" @default.
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• W2134262589 date "2015-10-01" @default.
• W2134262589 modified "2023-10-17" @default.
• W2134262589 title "Membrane Curvature-sensing and Curvature-inducing Activity of Islet Amyloid Polypeptide and Its Implications for Membrane Disruption" @default.
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• W2134262589 doi "https://doi.org/10.1074/jbc.m115.659797" @default.
• W2134262589 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4646232" @default.
• W2134262589 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26283787" @default.
• W2134262589 hasPublicationYear "2015" @default.

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