Identification of a novel human islet amyloid polypeptide β-sheet domain and factors influencing fibrillogenesis

Jaikaran, Emma T. A. S.; Higham, Claire; Serpell, Louise C.; Zurdo, Jesús; Gross, Michael L.; Clark, Anne; Fraser, Paul E.

doi:10.1006/jmbi.2001.4593

Cited by 227 publications

(242 citation statements)

References 28 publications

(40 reference statements)

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“…It is possible that the early β-sheets are limited to residues 23-27, which would be consistent with early fragment studies showing that hIAPP [23][24][25][26][27] is the smallest fragment of hIAPP capable of forming amyloid fibrils (15). However, the hIAPP 22-27 fragment aggregates 40 times faster than hIAPP [23][24][25][26][27] and hIAPP [20][21][22][23][24][25][26][27][28][29] aggregates faster still, suggesting that the oligomeric β-sheets might extend beyond our labeled region to include the serines (15). Nonetheless, we know that the β-sheets must be small because, like typical random coil peptides, the unlabeled region of the spectra has only a minimal peak at 1,620 cm −1 (and does not extend to V17 or G33).…”

Section: Resultssupporting

confidence: 68%

“…Molecular dynamics simulations corroborate the assembly of such fragments into β-sheet structures (18)(19)(20). Although other segments also form amyloid fibrils (21,22), the simplest explanation for the correlation between the sequence and propensity for fibril formation is that the region near 20-29 forms β-sheets that are the "amyloidogenic core" of the fibrils (14,15,17,23). This hypothesis is also consistent with many single-point mutations within residues 20-29 of hIAPP that can decrease or prevent fibril formation (23)(24)(25).…”

mentioning

confidence: 61%

“…Early work revealed a correlation between the ability to form amyloid in vitro and the sequence in the 20-29 region (13,14). The fragment hIAPP [20][21][22][23][24][25][26][27][28][29] (SNNFGAILSS) readily forms amyloid fibrils, as do smaller fragments such as hIAPP 23-27 (13-17) and hIAPP [21][22][23][24][25][26][27] ; the latter has been characterized with X-ray crystallography (5). Molecular dynamics simulations corroborate the assembly of such fragments into β-sheet structures (18)(19)(20).…”

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confidence: 99%

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Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient β-sheet

Buchanan

Dunkelberger

Tran

et al. 2013

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

245

345

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Amyloid formation is implicated in more than 20 human diseases, yet the mechanism by which fibrils form is not well understood. We use 2D infrared spectroscopy and isotope labeling to monitor the kinetics of fibril formation by human islet amyloid polypeptide (hIAPP or amylin) that is associated with type 2 diabetes. We find that an oligomeric intermediate forms during the lag phase with parallel β-sheet structure in a region that is ultimately a partially disordered loop in the fibril. We confirm the presence of this intermediate, using a set of homologous macrocyclic peptides designed to recognize β-sheets. Mutations and molecular dynamics simulations indicate that the intermediate is on pathway. Disrupting the oligomeric β-sheet to form the partially disordered loop of the fibrils creates a free energy barrier that is the origin of the lag phase during aggregation. These results help rationalize a wide range of previous fragment and mutation studies including mutations in other species that prevent the formation of amyloid plaques.inhibitors | aggregation pathway | vibrational coupling T he misfolding of proteins into β-sheet-rich amyloid fibrils is associated with the pathology of more than 20 human diseases, including Alzheimer's, Parkinson, and Huntington diseases (1). Amyloid plaques are formed by masses of fibrils, but growing evidence suggests that the toxic species may be prefibrillar intermediates (2, 3). As a result, there is much interest in understanding the mechanism by which these proteins form fibrils and identifying intermediates in the aggregation pathway. However, obtaining structural information about intermediate species is difficult due to their transient nature. Solid-state NMR (ssNMR) and X-ray crystallography provide high-resolution structures of fibrils (4, 5) and optical techniques can track structural changes in real time (6, 7), but few techniques have both the structural and the temporal resolution to extract specific structural details about intermediates. Fragments have been trapped in intriguing oligomeric structures that may represent intermediate states (5,8) and transient secondary structures are known to exist from circular dichroism measurements and other experiments (9-11), but for full-length proteins it has been difficult to identify the specific residues that contribute to the secondary structure and thus understand their role in the aggregation mechanism. In this paper, we use 2D infrared (2D IR) spectroscopy and isotope labeling to monitor the structural evolution of the full-length human islet amyloid polypeptide (hIAPP or amylin), a 37-residue peptide implicated in type 2 diabetes. We observe the formation of a structured prefibrillar intermediate in a region that has long been known to influence aggregation, but that does not form well-ordered cross-β structure in the amyloid fibril. Its presence provides unique structural insights into the mechanism of amyloid aggregation and helps unify many seemingly inconsistent prior studies.Many studies on hIAPP have focused ...

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Section: Resultssupporting

confidence: 68%

mentioning

confidence: 61%

mentioning

confidence: 99%

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Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient β-sheet

Buchanan

Dunkelberger

Tran

et al. 2013

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

245

345

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“…The hIAPP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] and hIAPP [20][21][22][23][24][25][26][27][28][29] peptides were synthesized using standard FMOC (9-fluornylmethoxycarbonyl) methods. A PAL-PEG resin was used to provide an amidated C-terminus.…”

Section: Methodsmentioning

confidence: 99%

“…After synthesis, the crude hIAPP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] peptide was subjected to air oxidation to form the disulfide bond. The identity of the hIAPP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] and hIAPP [20][21][22][23][24][25][26][27][28][29] sequences and formation of the disulfide bond for hIAPP [1][2][3][4][5][6]…”

Section: Methodsmentioning

confidence: 99%

Amyloid Fiber Formation and Membrane Disruption are Separate Processes Localized in Two Distinct Regions of IAPP, the Type-2-Diabetes-Related Peptide

et al. 2008

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Aggregation of Islet Amyloid Polypeptide (IAPP) has been implicated in the development of type II diabetes. Because IAPP is a highly amyloidogenic peptide, it has been suggested that the formation of IAPP amyloid fibers causes disruption of the cellular membrane and is responsible for the death of β-cells during type II diabetes. Previous studies have shown that the N-terminal 1-19 region, rather than the amyloidogenic 20-29 region, is primarily responsible for the interaction of the IAPP peptide with membranes. Liposome leakage experiments presented in this study confirm that the pathological membrane disrupting activity of the full-length hIAPP is also shared by hIAPP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] . The hIAPP 1-19 fragment at a low concentration of peptide induces membrane disruption to a near identical extent as the full-length peptide. At higher peptide concentrations, the hIAPP 1-19 fragment induces a greater extent of membrane disruption than the full-length peptide. Similar to the full-length peptide, hIAPP 1-19 exhibits a random coil conformation in solution and adopts an α-helical conformation upon binding to lipid membranes. However, unlike the full-length peptide, the hIAPP 1-19 fragment did not form amyloid fibers when incubated with POPG vesicles. These results indicate that membrane disruption can occur independently from amyloid formation in IAPP, and the sequences responsible for amyloid formation and membrane disruption are located in different regions of the peptide.

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Amyloidogenicity and cytotoxicity of islet amyloid polypeptide

Kapurniotu

2001

Biopolymers

116

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Insoluble amyloid formation by islet amyloid polypeptide (IAPP) in the islets of Langerhans of the pancreas is a major pathophysiological feature of noninsulin dependent diabetes mellitus (NIDDM) or type II diabetes. Because in vivo formed amyloid colocalizes with areas of cell degeneration and IAPP amyloid aggregates are cytotoxic per se, the process of IAPP amyloid formation has been strongly associated with the progressive pancreatic cell degeneration and thus much of the pathology of type II diabetes. IAPP is a pancreatic polypeptide of 37 residues that, in its soluble form, is believed to play a role as a regulator of glucose homeostasis. The molecular cause and mechanism of the conversion of soluble IAPP into insoluble amyloid aggregates in vivo and its role in disease progress still remain to be clarified. Nevertheless, in the past few years significant progress has been made in understanding the amyloidogenesis pathway of IAPP in vitro and gaining insight into the structural and conformational “requirements” of IAPP amyloidogenesis and related cytotoxic effects. Importantly, several of the studies have revealed significant similarities of the above features of IAPP to other amyloidogenic polypeptides such as the β‐amyloid polypeptide Aβ. This suggests that, at the molecular level, amyloidogenesis, and possibly related cell degeneration and disease pathogenesis by completely different polypeptide sequences, may obey to common structural and conformational “rules” and follow similar molecular pathways. This review describes studies on the structural and conformational features of IAPP amyloid formation and cytotoxicity, and the application of the obtained knowledge for the understanding of the molecular mechanism of the IAPP amyloidogenesis pathway and the related cytotoxicity. © 2002 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 60: 438–459, 2001

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Identification of a novel human islet amyloid polypeptide β-sheet domain and factors influencing fibrillogenesis

Cited by 227 publications

References 28 publications

Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient β-sheet

Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient β-sheet

Amyloid Fiber Formation and Membrane Disruption are Separate Processes Localized in Two Distinct Regions of IAPP, the Type-2-Diabetes-Related Peptide

Amyloidogenicity and cytotoxicity of islet amyloid polypeptide

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