Human Islet Amyloid Polypeptide Monomers Form Ordered β-hairpins: A Possible Direct Amyloidogenic Precursor

Dupuis, Nicholas; Wu, Chun; Shea, Joan–Emma; Bowers, Michael T.

doi:10.1021/ja903814q

Cited by 212 publications

(373 citation statements)

References 74 publications

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“…Three stable conformations of the monomer can be identified by the minima in that surface; these conformations are the same as those described in previous works. 28,29 The relative values of the free energy for the three structures, which were estimated here on the basis of metadynamics simulations, are in quantitative agreement (within 1 kJ/mol) with those calculated in our earlier work on the basis of thermodynamic integration. 28 The new crucial piece of information included in Figure 2, which was not available in previous work, corresponds to the free energy landscape that surrounds those minima.…”

Section: A Free Energy Mapsupporting

confidence: 82%

“…That behavior is evident in simulations using explicit water 28 or an implicit solvent. 29,30 Our own view is that specific residues could play a key role in the pathways for inter-conversion between them, and that such conformational transitions could in fact constitute the nucleation event. Studies of long polyglutamine molecules are consistent with that view, 31 but comparable studies of conformational transition pathways in amylin have not been carried out before.…”

Section: Introductionmentioning

confidence: 99%

“…16,[33][34][35][36][37] Recent NMR studies on human amylin, 38 rat amylin and pramlintide peptides, which have sequences similar to that of amylin, suggest that an α-helical structure is adopted near the N-terminus. 39,40 By interpreting the results of ion mobility mass spectroscopy experiments with a molecular implicit-solvent model, Dupuis et al 29 showed that the hIAPP monomer adopts an α-helical conformation between residues 9-17 on the terminus end, and a short β-hairpin between residues 24-28 and 31-35 on the C-terminus. Using a combination of 2DIR experiments and an atomistic explicit-water model, Reddy et al 28 reported similar conformations to those reported by Dupuis et al 29 Note that previous experiments in the presence of membranes also proposed an α-helical secondary structure for the human amylin protein.…”

Section: Introductionmentioning

confidence: 99%

“…39,40 By interpreting the results of ion mobility mass spectroscopy experiments with a molecular implicit-solvent model, Dupuis et al 29 showed that the hIAPP monomer adopts an α-helical conformation between residues 9-17 on the terminus end, and a short β-hairpin between residues 24-28 and 31-35 on the C-terminus. Using a combination of 2DIR experiments and an atomistic explicit-water model, Reddy et al 28 reported similar conformations to those reported by Dupuis et al 29 Note that previous experiments in the presence of membranes also proposed an α-helical secondary structure for the human amylin protein. 15,19,41 The aim of the present study is to use simulations in an explicit water model to arrive at a detailed molecular picture of the inter-conversion pathways of human amylin between the α-helical, β-hairpin, and unstructured coil states.…”

Section: Introductionmentioning

confidence: 99%

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α-helix to β-hairpin transition of human amylin monomer

Singh

Chiu

Reddy

et al. 2013

The Journal of Chemical Physics

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The human islet amylin polypeptide is produced along with insulin by pancreatic islets. Under some circumstances, amylin can aggregate to form amyloid fibrils, whose presence in pancreatic cells is a common pathological feature of Type II diabetes. A growing body of evidence indicates that small, early stage aggregates of amylin are cytotoxic. A better understanding of the early stages of the amylin aggregation process and, in particular, of the nucleation events leading to fibril growth could help identify therapeutic strategies. Recent studies have shown that, in dilute solution, human amylin can adopt an α-helical conformation, a β-hairpin conformation, or an unstructured coil conformation. While such states have comparable free energies, the β-hairpin state exhibits a large propensity towards aggregation. In this work, we present a detailed computational analysis of the folding pathways that arise between the various conformational states of human amylin in water. A free energy surface for amylin in explicit water is first constructed by resorting to advanced sampling techniques. Extensive transition path sampling simulations are then employed to identify the preferred folding mechanisms between distinct minima on that surface. Our results reveal that the α-helical conformer of amylin undergoes a transformation into the β-hairpin monomer through one of two mechanisms. In the first, misfolding begins through formation of specific contacts near the turn region, and proceeds via a zipping mechanism. In the second, misfolding occurs through an unstructured coil intermediate. The transition states for these processes are identified. Taken together, the findings presented in this work suggest that the inter-conversion of amylin between an α-helix and a β-hairpin is an activated process and could constitute the nucleation event for fibril growth.

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Section: A Free Energy Mapsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

α-helix to β-hairpin transition of human amylin monomer

Singh

Chiu

Reddy

et al. 2013

The Journal of Chemical Physics

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“…The conformational stabilities of the wild-type and R5A mutant-type Aβ42 peptides were calculated utilizing the molecular mechanics/generalized Born surface area (MM/GBSA) method. 35,49,50 The MM/GBSA method determines the conformational Gibbs free energy (G) from the potential energy (E MM ), the solvation free energy (G sol ), and the entropy (S) at a specific temperature (T) via eq 1.…”

Section: ■ Methodsmentioning

confidence: 99%

Arginine and Disordered Amyloid-β Peptide Structures: Molecular Level Insights into the Toxicity in Alzheimer’s Disease

Coskuner

Wise-Scira

2013

ACS Chem. Neurosci.

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Recent studies present that the single arginine (R) residue in the sequence of Aβ42 adopts abundant β-sheet structure and forms stable salt bridges with various residues. Furthermore, experiments proposed that R stimulates the Aβ assembly and arginine (R) to alanine (A) mutation (R5A) decreases both aggregate formation tendency and the degree of its toxicity. However, the exact roles of R and R5A mutation in the structures of Aβ42 are poorly understood. Extensive molecular dynamics simulations along with thermodynamic calculations present that R5A mutation impacts the structures and free energy landscapes of the aqueous Aβ42 peptide. The β-sheet structure almost disappears in the Ala21−Ala30 region but is more abundant in parts of the central hydrophobic core and C-terminal regions of Aβ42 upon R5A mutation. More abundant α-helix is adopted in parts of the N-terminal and mid-domain regions and less prominent α-helix formation occurs in the central hydrophobic core region of Aβ42 upon R5A mutation. Interestingly, intramolecular interactions between N-and C-terminal or mid-domain regions disappear upon R5A mutation. The structures of Aβ42 are thermodynamically less stable and retain reduced compactness upon R5A mutation. R5A mutant-type structure stability increases with more prominent central hydrophobic core and mid-domain or C-terminal region interactions. Based on our results reported in this work, small organic molecules and antibodies that avoid β-sheet formation in the Ala21−Ala30 region and hinder the intramolecular interactions occurring between the N-terminal and mid-domain or C-terminal regions of Aβ42 may help to reduce Aβ42 toxicity in Alzheimer's disease.

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A Membrane‐Bound Antiparallel Dimer of Rat Islet Amyloid Polypeptide

2011

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Islet amyloid polypeptide (IAPP, also known as amylin) is a 37-residue peptide hormone co-secreted with insulin by pancreatic b cells. IAPP is natively unstructured, but gains a-helical structure on binding to anionic membranes [1] and forms b-sheet-rich amyloid fibers during the progression of type II diabetes. [2] Membrane disruption by nonfibrillar ahelical oligomers of IAPP has been implicated in b-cell death and dysfunction. [3] Anionic membranes also dramatically accelerate the formation of IAPP fibrils, [4] possibly by favoring an oligomeric nucleating state. Therefore, membrane-bound states of IAPP are of significant interest. [5] Lipid-bound monomeric IAPP has been structurally characterized at high resolution, [6, 7] but oligomers are dynamic, heterogeneous, and transient, thus presenting a challenge for traditional structure determination approaches. Several research groups have studied these oligomeric states, [8,9] but fundamental questions about their topology and stoichiometry remain.We approached this problem by using intermolecular single-pair Fçrster resonance energy transfer (spFRET) measurements to selectively study membrane-bound IAPP oligomers from a predominantly monomeric population. To avoid experimental complications arising from fiber formation, we used the rat isoform of IAPP (rIAPP), which differs from the human isoform (hIAPP) in six residues. Similar to hIAPP, rIAPP can cause membranes to become permeable [10] and causes cell toxicity, [11] but it does not form amyloid. [12] The rIAPP was labeled with either a single donor (Alexa 488) at one of five residues, or an acceptor (Atto 610) at residue 1 ( Figure 1). Measurements were made in a dilute mixture of labeled rIAPP and 1,2-dioleoyl-sn-glycero-3-[phospho-rac-(1glycerol)] (DOPG) nanodiscs [13] as the particles diffused through a focused laser beam. The energy-transfer efficiency (ET eff ) was calculated for each transit of a fluorescent particle through the focal volume. Energy transfer only occurs when at least one donor-labeled and one acceptor-labeled rIAPP are bound to the same nanodisc (see Figure S1c in the Supporting Information). Intramolecular spFRET using double-labeled rIAPP served to verify the expected conversion from a compact disordered state in solution to a helical state in the presence of membranes (Figure 1 F).Under our experimental conditions, we expected rIAPP to be largely monomeric (free in solution or membranebound) as reflected by the major peak centered at ET eff = 0 in all histograms (Figure 1 A-E). A minor but significant population of events with ET eff > 0.25 (ca. 0.5 %) results from nanodiscs containing at least one donor-acceptor rIAPP pair. Residue pairs 1-36 and 1-1 displayed the highest peak ET eff , followed by 1-22, 1-30, and 1-17. As an Figure 1. A-E) spFRET histograms collected from a mixture of rIAPP, separately labeled with donor (d) or acceptor (a) at the positions indicated, and nanodiscs. A small fraction of rIAPP forms membranebound dimers, and the minor species ET eff peak reports on...

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Human Islet Amyloid Polypeptide Monomers Form Ordered β-hairpins: A Possible Direct Amyloidogenic Precursor

Cited by 212 publications

References 74 publications

α-helix to β-hairpin transition of human amylin monomer

α-helix to β-hairpin transition of human amylin monomer

Arginine and Disordered Amyloid-β Peptide Structures: Molecular Level Insights into the Toxicity in Alzheimer’s Disease

A Membrane‐Bound Antiparallel Dimer of Rat Islet Amyloid Polypeptide

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