Amyloidogenic Propensities and Conformational Properties of ProIAPP and IAPP in the Presence of Lipid Bilayer Membranes

Jha, Suman; Sellin, Daniel; Seidel, R.; Winter, Roland

doi:10.1016/j.jmb.2009.04.077

Cited by 73 publications

(64 citation statements)

References 46 publications

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“…We examined two more complicated model systems: total brain extract lipids (TBE-lipids) and a ternary system consisting of DOPC, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol at a 1:2:1 ratio. TBE-lipids have been widely used as models of the plasma membrane and have been used in studies of IAPP-membrane interactions (28,(39)(40)(41). They are considerably more complex than standard one-or two-component model membrane systems.…”

Section: Folded Monomeric Proteins Are Less Effective At Inducing Modelmentioning

confidence: 99%

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Islet amyloid polypeptide toxicity and membrane interactions

Cao

Abedini

Wang

et al. 2013

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

130

143

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Islet amyloid polypeptide (IAPP) is responsible for amyloid formation in type 2 diabetes and contributes to the failure of islet cell transplants, however the mechanisms of IAPP-induced cytotoxicity are not known. Interactions with model anionic membranes are known to catalyze IAPP amyloid formation in vitro. Human IAPP damages anionic membranes, promoting vesicle leakage, but the features that control IAPP-membrane interactions and the connection with cellular toxicity are not clear. Kinetic studies with wildtype IAPP and IAPP mutants demonstrate that membrane leakage is induced by prefibrillar IAPP species and continues over the course of amyloid formation, correlating additional membrane disruption with fibril growth. Analyses of a set of designed mutants reveal that membrane leakage does not require the formation of β-sheet or α-helical structures. A His-18 to Arg substitution enhances leakage, whereas replacement of all of the aromatic residues via a triple leucine mutant has no effect. Biophysical measurements in conjunction with cytotoxicity studies show that nonamyloidogenic rat IAPP is as effective as human IAPP at disrupting standard anionic model membranes under conditions where rat IAPP does not induce cellular toxicity. Similar results are obtained with more complex model membranes, including ternary systems that contain cholesterol and are capable of forming lipid rafts. A designed point mutant, I26P-IAPP; a designed double mutant, G24P, I26P-IAPP; a double N-methylated variant; and pramlintide, a US Food and Drug Administration-approved IAPP variant all induce membrane leakage, but are not cytotoxic, showing that there is no one-to-one relationship between disruption of model membranes and induction of cellular toxicity.

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Section: Folded Monomeric Proteins Are Less Effective At Inducing Modelmentioning

confidence: 99%

“…The DOPC, DPPC, cholesterol system can form lipid rafts and has been used in other studies of IAPP-model membrane interactions (28,39,40). Amyloid formation by wild-type hIAPP is accelerated by this membrane.…”

Section: Folded Monomeric Proteins Are Less Effective At Inducing Modelmentioning

confidence: 99%

Islet amyloid polypeptide toxicity and membrane interactions

Cao

Abedini

Wang

et al. 2013

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

130

143

View full text Add to dashboard Cite

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“…Subsequent CD studies demonstrated that the hIAPP monomer adopts primarily a random coil structure. 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.…”

Section: Introductionmentioning

confidence: 99%

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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“…Besides membranes, it is known that other factors can play important roles in the aggregation process of hIAPP, such as pH, metal ions, ionic strength and other protein components (e.g. insulin, C-peptide, proinsulin and pro-amylin) [27][28][29][30][31]. In the physiological range, acidic pH has been shown to inhibit fibrillation of hIAPP in vitro, whereas basic pH promotes the fibril formation [27,[31][32][33].…”

Section: Introductionmentioning

confidence: 99%

Human islet amyloid polypeptide at the air–aqueous interface: a Langmuir monolayer approach

Mićić

Orbulescu

et al. 2012

J. R. Soc. Interface.

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Human islet amyloid polypeptide (hIAPP) is the source of the major component of the amyloid deposits found in the islets of Langerhans of around 95 per cent type 2 diabetic patients. The formation of aggregates and mature fibrils is thought to be responsible for the dysfunction and death of the insulin-producing pancreatic b-cells. Investigation on the conformation, orientation and self-assembly of the hIAPP at time zero could be beneficial for our understanding of its stability and aggregation process. To obtain these insights, the hIAPP at time zero was studied at the air-aqueous interface using the Langmuir monolayer technique. The properties of the hIAPP Langmuir monolayer at the air -aqueous interface on a NaCl subphase with pH 2.0, 5.6 and 9.0 were examined by surface pressure-and potential-area isotherms, UV-Vis absorption, fluorescence spectroscopy and Brewster angle microscopy. The conformational and orientational changes of the hIAPP Langmuir monolayer under different surface pressures were characterized by p-polarized infrared-reflection absorption spectroscopy, and the results did not show any prominent changes of conformation or orientation. The predominant secondary structure of the hIAPP at the air -aqueous interface was a-helix conformation, with a parallel orientation to the interface during compression. These results showed that the hIAPP Langmuir monolayer at the air -aqueous interface was stable, and no aggregate or domain of the hIAPP at the air -aqueous interface was observed during the time of experiments.

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Amyloidogenic Propensities and Conformational Properties of ProIAPP and IAPP in the Presence of Lipid Bilayer Membranes

Cited by 73 publications

References 46 publications

Islet amyloid polypeptide toxicity and membrane interactions

Islet amyloid polypeptide toxicity and membrane interactions

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

Human islet amyloid polypeptide at the air–aqueous interface: a Langmuir monolayer approach

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