Islet Amyloid Polypeptide Forms Rigid Lipid–Protein Amyloid Fibrils on Supported Phospholipid Bilayers

Domanov, Yegor A.; Kinnunen, Paavo K.J.

doi:10.1016/j.jmb.2007.11.077

Cited by 99 publications

(123 citation statements)

References 58 publications

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“…Using fluorescence methods, Reynolds et al (12) observed fibril growth and lipid extraction/thinning by adding monomeric α-synuclein to membranes supported on a solid surface. In a similar study it was shown that addition of islet-associated polypeptide (IAPP) induces defects on supported lipid bilayers, accompanied by transfer of lipid vesicles onto growing amyloid fibrils (14). These studies provide a large body of evidence suggesting a significant involvement of lipid membranes in amyloid cytotoxicity.…”

Section: Discussionmentioning

confidence: 88%

“…In some systems, there is evidence suggesting that prefibrillar oligomers, rather than the fully formed fibrils, are the source of toxicity (8,9). In these cases, cytotoxicity is thought to result from the formation of specific membrane pores (10,11) although alternative models including membrane destabilization or membrane thinning have also been proposed (12)(13)(14)(15). In other cases, toxicity may reside with the amyloid fibrils themselves.…”

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confidence: 99%

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Direct three-dimensional visualization of membrane disruption by amyloid fibrils

Milanesi

Sheynis

Xue

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

167

172

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Protein misfolding and aggregation cause serious degenerative conditions such as Alzheimer's, Parkinson, and prion diseases. Damage to membranes is thought to be one of the mechanisms underlying cellular toxicity of a range of amyloid assemblies. Previous studies have indicated that amyloid fibrils can cause membrane leakage and elicit cellular damage, and these effects are enhanced by fragmentation of the fibrils. Here we report direct 3D visualization of membrane damage by specific interactions of a lipid bilayer with amyloid-like fibrils formed in vitro from β 2 -microglobulin (β 2 m). Using cryoelectron tomography, we demonstrate that fragmented β 2 m amyloid fibrils interact strongly with liposomes and cause distortions to the membranes. The normally spherical liposomes form pointed teardrop-like shapes with the fibril ends seen in proximity to the pointed regions on the membranes. Moreover, the tomograms indicated that the fibrils extract lipid from the membranes at these points of distortion by removal or blebbing of the outer membrane leaflet. Tiny (15-25 nm) vesicles, presumably formed from the extracted lipids, were observed to be decorating the fibrils. The findings highlight a potential role of fibrils, and particularly fibril ends, in amyloid pathology, and report a previously undescribed class of lipid-protein interactions in membrane remodelling.T he failure of molecular chaperones to prevent the accumulation of misfolded proteins results in protein aggregation and amyloid formation, processes associated with severe human degenerative diseases (1, 2). Despite the attention focused on these problems during the century since these disorders were first identified (3-5) and advances in understanding the structure of the cross-β conformation of amyloid fibrils in atomic detail (6, 7), the basic pathological mechanisms of amyloidosis remain poorly understood and therapeutic intervention is lacking. The identity of the toxic species and the mechanisms of cytotoxicity remain major unsolved problems. In some systems, there is evidence suggesting that prefibrillar oligomers, rather than the fully formed fibrils, are the source of toxicity (8, 9). In these cases, cytotoxicity is thought to result from the formation of specific membrane pores (10, 11) although alternative models including membrane destabilization or membrane thinning have also been proposed (12-15). In other cases, toxicity may reside with the amyloid fibrils themselves. Evidence that toxicity correlates with fibrillar assemblies has been reported for yeast and mammalian prion proteins (16, 17), human lysozyme (18), Huntingtin exon 1, α-synuclein (19), and Amyloid-β (Aβ) (20, 21). Furthermore, Aβ plaques have been shown to form rapidly in vivo and to precede neuropathological changes in a mouse model (22). The end surfaces of fibrils (herein termed "fibril ends") are unusually reactive entities: they play a key role in catalyzing recruitment and conformational conversion of amyloid-forming proteins (23, 24) and provide the sites for templated...

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Section: Discussionmentioning

confidence: 88%

mentioning

confidence: 99%

Direct three-dimensional visualization of membrane disruption by amyloid fibrils

Milanesi

Sheynis

Xue

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

167

172

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show abstract

“…However, compared with the study in bulk solution, the study at lipid membrane interface should be more important because hIAPP-induced toxicity in diabetes involves interactions between the cell membrane and misfolded protein. Many studies using phospholipids as model membranes have demonstrated that hIAPP binds strongly to lipid membranes [13][14][15][16][17][18][19], in particular to anionic membranes [18,20]. Moreover, the activity and mechanism of inhibition at membrane interface may be quite different from those in bulk solution.…”

Section: Introductionmentioning

confidence: 99%

A hIAPP‐derived all‐d‐amino‐acid inhibits hIAPP fibrillation efficiently at membrane surface by targeting α‐helical oligomeric intermediates

Wang

Lei

et al. 2014

FEBS Letters

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Edited by Sandro Sonnino ) is demonstrated to inhibit hIAPP fibril formation efficiently both at the phospholipid membrane and in bulk solution. The inhibitor terminates hIAPP aggregation to the a-helical oligomeric intermediates at the membrane surface, whereas it stops the aggregation at the stage of b-sheet oligomeric intermediates in bulk solution. This is the first evidence that the inhibition mechanism of the inhibitor at membrane surface is significantly different from that in bulk solution. Structured summary of protein interactions:hIAPP and hIAPP bind by transmission electron microscopy (View interaction) hIAPP and hIAPP bind by atomic force microscopy (View interaction) hIAPP and hIAPP bind by fluorescence technology (View interaction) hIAPP and hIAPP bind by dynamic light scattering (View interaction)

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“…Accumulating evidence has suggested that membrane lipids play a crucial role in the formation of amyloid fibrils [10]. Experiments in vitro demonstrated that two negatively charged lipid species, phosphatidylglycerol (PG) [11], and phosphatidylserine (PS) [12], significantly facilitate the production of amyloid by hIAPP. However, neither lipid is expressed in the outer leaflets of plasma membranes of mammalian cells.…”

Section: Introductionmentioning

confidence: 99%

Ganglioside‐induced amyloid formation by human islet amyloid polypeptide in lipid rafts

Wakabayashi¹,

Matsuzaki²

2009

FEBS Letters

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Edited by Jesus Avila Keywords:Human islet amyloid polypeptide Amyloid fibril Ganglioside Cholesterol Lipid raft a b s t r a c t Human islet amyloid polypeptide (hIAPP) is the primary component of the amyloid deposits found in the pancreatic islets of patients with type 2 diabetes mellitus. However, it is unknown how amyloid fibrils are formed in vivo. In this study, we demonstrate that gangliosides play an essential role in the formation of amyloid deposits by hIAPP on plasma membranes. Amyloid fibrils accumulated in ganglioside-and cholesterol-rich microscopic domains ('lipid rafts'). The depletion of gangliosides or cholesterol significantly reduced the amount of amyloid deposited. These results clearly showed that the formation of amyloid fibrils was mediated by gangliosides in lipid rafts.

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Islet Amyloid Polypeptide Forms Rigid Lipid–Protein Amyloid Fibrils on Supported Phospholipid Bilayers

Cited by 99 publications

References 58 publications

Direct three-dimensional visualization of membrane disruption by amyloid fibrils

Direct three-dimensional visualization of membrane disruption by amyloid fibrils

A hIAPP‐derived all‐d‐amino‐acid inhibits hIAPP fibrillation efficiently at membrane surface by targeting α‐helical oligomeric intermediates

Ganglioside‐induced amyloid formation by human islet amyloid polypeptide in lipid rafts

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