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See detailRole of the polyQ length and non-polyQ regions during the aggregation process into amyloid fibrils of model polyQ proteins
Huynen, Céline ULg; Willet, Nicolas ULg; Buell, Alexander K et al

Poster (2014, November 26)

Nine neurodegenerative disorders, referred to as polyglutamine diseases and including Huntington’s disease, are associated with the abnormal expansion of a polyglutamine tract inside nine unrelated ... [more ▼]

Nine neurodegenerative disorders, referred to as polyglutamine diseases and including Huntington’s disease, are associated with the abnormal expansion of a polyglutamine tract inside nine unrelated proteins. This polyQ expansion is thought to be the major determinant in the development of neurotoxicity, triggering protein aggregation into amyloid fibrils. A large body of evidence however suggests that non-polyQ regions modulate the aggregation process triggered by polyQ expansions. The interplay between the polyQ tract and non-polyQ regions is complex and still not fully understood. In order to better understand it, we previously designed and characterized model polyQ proteins made of the beta-lactamase BlaP with 23, 30, 55 and 79Q inserted at position 197 or 216. Our first results had indicated that our model is relevant to study polyQ aggregation since it recapitulates the aggregation properties of polyQ disease-associated proteins: there is a Q-threshold for the spontaneous formation of amyloid fibrils in solution, and above the threshold, the longer the polyQ, the faster the aggregation. Moreover, the structure of BlaP and the position of insertion of the polyQ tract influence their aggregation properties in solution. This work aims to better understand, at the molecular level, (i) the precise role of the polyQ length (23, 30, 55, 61, 67, 73 and 79Q), (ii) the conformation of the host protein (native or unfolded BlaP), (iii) the location of the polyQ tract within BlaP (197 or 216), (iv) the flexibility of the polyQ flanking sequences, and (v) the origin of constraints applied by BlaP to the inserted polyQ tract (at its N- or C-terminal end) on the structural, thermodynamic and aggregation properties of BlaP-polyQ chimeras, using a wide range of biophysical techniques (e.g., spectroscopy methods, quartz crystal microbalance, atomic force microscopy and dynamic light scattering). The effect on the aggregation properties will be determined on the spontaneous aggregation into amyloid fibrils in solution, and on the nucleation and on the elongation steps of amyloid fibril formation. For this purpose, new chimeras containing 61, 67 and 73Q at position 197, or 55Q inserted at position 197 in between two different protease’s cleavage sites, that are relatively flexible, will be moreover created. Our results first demonstrate that the spontaneous aggregation into amyloid fibrils in solution is correlated to the polyQ length with an exponential growth function, and that the elongation rate is linearly correlated to the polyQ length, independently of the protein context (i.e., conformation of BlaP, and/or location of the polyQ tract, and/or polyQ peptides inserted or not within BlaP). However, the location of the polyQ tract inside BlaP, and/or its conformational state, and/or the flexibility of polyQ flanking sequences, and/or the origin of constraints applied to the polyQ tract drastically influence the ability of a polyQ tract to trigger the nucleation and/or the elongation step of amyloid fibrils (variation in the Q-threshold and in the absolute rate of both steps). Altogether, our results suggest that non-polyQ regions constitute an additional potential therapeutic target, more specific than drugs targeting the polyQ sequence, to interfere with the nucleation and/or the elongation of amyloid fibrils, associated to neurotoxicity. A possible drug could be constituted by a ligand specific to non-polyQ regions of disease-associated proteins, which further increases the constraints applied to the polyQ expansion to prevent the disease onset and/or progression. [less ▲]

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See detailRole of non-polyQ regions on the aggregation process by polyQ proteins into amyloid fibrils
Huynen, Céline ULg; Willet, Nicolas ULg; Buell, Alexander K et al

Poster (2014, October 18)

Nine neurodegenerative disorders, referred to as polyglutamine diseases and including Huntington’s disease, are associated with the abnormal expansion of a polyglutamine tract inside nine unrelated ... [more ▼]

Nine neurodegenerative disorders, referred to as polyglutamine diseases and including Huntington’s disease, are associated with the abnormal expansion of a polyglutamine tract inside nine unrelated proteins. This polyQ expansion is thought to be the major determinant in the development of neurotoxicity, triggering protein aggregation into amyloid fibrils. A large body of evidence however indicates that non-polyQ regions modulate the aggregation process triggered by polyQ expansions. The interplay between the polyQ tract and non-polyQ regions is complex and still not fully understood. In order to better understand it, we previously designed and characterized model polyQ proteins made of the beta-lactamase BlaP and a 23, 30, 55 or 79Q tract inserted in position 197 or 216. These chimeras recapitulate the aggregation properties of polyQ disease-associated proteins: there is a Q-threshold for the formation of amyloid fibrils, and above the threshold, the longer the polyQ, the faster the aggregation. Moreover, the structure of BlaP (native or unfolded) and the position of insertion of the polyQ tract (197 versus 216) influence their aggregation properties. In this work, (i) we discuss the role of the conformation of the host protein, BlaP, and of the location of the polyQ within BlaP on the different phases of amyloid fibril formation, the nucleation and elongation steps, using mainly quartz crystal microbalance (QCM), atomic force microscopy (AFM). Our results highlight a linear dependence of the polyQ length on the elongation rate whatever the insertion site and the conformation of BlaP. These two parameters however drastically influence the ability of a polyQ tract to trigger the nucleation and the elongation steps of amyloid fibril formation. (ii) Finally, we investigate the precise aggregation threshold and the modulating role of the N- and C-terminal polyQ flanking sequences in position 197 of BlaP by creating and characterizing new chimeras containing intermediate length polyQ tracts in position 197, or polyQ tracts inserted between two cleavage sites in position 197, respectively. We observe that the propensity to trigger the full process of amyloid fibril formation and its rate seems to be largely dependent on the polyQ length and on the polyQ flanking sequences. Altogether our results contribute to identify the important species and elements (polyQ or non-polyQ regions, monomers, oligomers or fibrils) during the aggregation process into amyloid fibrils to interfere with the latter associated with neurotoxicity. [less ▲]

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See detailRole of non-polyQ regions on the aggregation process by polyQ proteins into amyloid fibrils
Huynen, Céline ULg; Willet, Nicolas ULg; Buell, Alexander K et al

Poster (2014, July 28)

Nine neurodegenerative disorders, referred to as polyglutamine diseases and including Huntington’s disease, are associated with the abnormal expansion of a polyglutamine tract inside nine unrelated ... [more ▼]

Nine neurodegenerative disorders, referred to as polyglutamine diseases and including Huntington’s disease, are associated with the abnormal expansion of a polyglutamine tract inside nine unrelated proteins. This polyQ expansion is thought to be the major determinant in the development of neurotoxicity, triggering protein aggregation into amyloid fibrils. A large body of evidence however indicates that non-polyQ regions modulate the aggregation process triggered by polyQ expansions. The interplay between the polyQ tract and non-polyQ regions is complex and still not fully understood. In order to better understand it, we previously designed and characterized model polyQ proteins made of the beta-lactamase BlaP and a 23, 30, 55 or 79Q tract inserted in position 197 or 216. These chimeras recapitulate the aggregation properties of polyQ disease-associated proteins: there is a Q threshold for the formation of amyloid fibrils, and above the threshold, the longer the polyQ, the faster the aggregation. Moreover, the structure of BlaP (native or unfolded) and the position of insertion of the polyQ tract (197 versus 216) influence their aggregation properties. In this work, (i) we will discuss the role of the conformation of the host protein, BlaP, and of the location of the polyQ within BlaP on the different phases of amyloid fibril formation, the nucleation and elongation steps, using mainly quartz crystal microbalance (QCM), atomic force microscopy (AFM) and dynamic light scattering (DLS); and (ii) we will investigate the precise aggregation threshold and the modulating role of the N- and C-terminal polyQ flanking sequences in position 197 of BlaP by creating and characterizing new chimeras containing intermediate length polyQ tracts in position 197, or polyQ tracts inserted between two cleavage sites in position 197, respectively. Our results highlight a linear dependence of the polyQ length on the elongation rate whatever the insertion site and the conformation of BlaP. These two parameters however drastically influence the ability of a polyQ tract to trigger the nucleation and the elongation steps of amyloid fibril formation. Finally, we observed that the propensity to form amyloid fibrils and its rate seems to be largely dependent on the polyQ length and on the polyQ flanking sequences. Altogether our results contribute to identify the important species and elements (polyQ or non-polyQ regions, monomers, oligomers or fibrils) during the aggregation process into amyloid fibrils to interfere with the latter associated with neurotoxicity. [less ▲]

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See detailSwitching to the Dark Side: Repositioning of Polyglutamine Repeat Promotes Amyloid Fibril Formation by the Model Protein, β-Lactamase BlaP
Thorn, David ULg; Pain, Coralie ULg; Scarafone, Natacha et al

Conference (2013, November 20)

Background: The expansion of polyglutamine (polyQ) repeats is associated with an increased propensity of the protein to aggregate into amyloid fibrils. There are ten human proteins presently known within ... [more ▼]

Background: The expansion of polyglutamine (polyQ) repeats is associated with an increased propensity of the protein to aggregate into amyloid fibrils. There are ten human proteins presently known within which polyQ expansion above a threshold length, e.g. 35-50 residues, leads to ten distinct neurodegenerative disorders [1], the most well-known being Huntington’s disease. While repeat length, aggregation, and disease are well correlated, recent studies suggest the non-polyQ regions of these proteins can also play a significant role, both preventative and facilitative, in the aggregation process. With the aim of exploring this role in more detail, we have engineered chimeric proteins via the insertion of polyQ repeats of various length (23, 30, 55, 79 Q) into two sites of antibiotic resistance enzyme BlaP β-lactamase from Bacillus licheniformis 749/C [2]. Questions addressed: How does polyQ repeat position affect the structure, stability and aggregation of polyQ proteins? Methods: Aggregation kinetics determined by monitoring the decrease in soluble protein fraction over time. Aggregate morphology examined by transmission electron microscopy. Protein stability derived from thermal or chemical unfolding transitions monitored by far-UV CD and intrinsic fluorescence. Results and discussion: PolyQ insertion at either of the two positions led to a decrease in thermodynamic stability that was largely independent of polyQ length. Chimeras with polyQ insertions at position 216 were destabilised to a much greater extent than those with insertions at position 197. The reduced stability of the 216 chimeras was associated with an increased aggregation propensity: (i) the minimum polyQ length leading to aggregation was lower, and (ii) the aggregation rate was significantly higher than that observed by 197 chimeras with equivalent polyQ lengths. Remarkably, the two sites of polyQ insertion are indeed very similar, both residing within flexible loop regions between stable α-helices. Moreover, the 216 chimeras exhibited a higher aggregation propensity than their 197 counterparts even under denaturing conditions, suggesting the disparity between the two chimeras cannot be accounted for by structural differences alone. These findings highlight the strong and complex influence of the overall protein context on polyQ-mediated aggregation. The molecular basis for the observed changes in stability and aggregation propensity is the subject of on-going work. [less ▲]

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See detailClass A β -Lactamases as Versatile Scaffolds to Create Hybrid Enzymes: Applications from Basic Research to Medicine
Huynen, Céline ULg; Filée, Patrice; Matagne, André ULg et al

in BioMed Research International (2013), 2013

Designing hybrid proteins is a major aspect of protein engineering and covers a very wide range of applications frombasic research to medical applications. This review focuses on the use of class A 𝛽 ... [more ▼]

Designing hybrid proteins is a major aspect of protein engineering and covers a very wide range of applications frombasic research to medical applications. This review focuses on the use of class A 𝛽-lactamases as versatile scaffolds to design hybrid enzymes (referred to as 𝛽-lactamase hybrid proteins, BHPs) in which an exogenous peptide, protein or fragment thereof is inserted at various permissive positions.We discuss how BHPs can be specifically designed to create bifunctional proteins, to produce and to characterize proteins that are otherwise difficult to express, to determine the epitope of specific antibodies, to generate antibodies against nonimmunogenic epitopes, and to better understand the structure/function relationship of proteins. [less ▲]

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See detailA Nanobody Binding to Non-amyloidogenic Regions of the Protein Human Lysozyme Enhances Partial Unfolding but Inhibits Amyloid Fibril Formation.
de Genst, EJ; Chan, PH; Pardon, Els et al

in Journal of Physical Chemistry B (2013)

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See detailNanobodies as structural probes to investigate the mechanism of fibril formation by the amyloidogenic variants of human lysozyme
Dumont, Janice ULg; pardon, Els; Aumont-Nicaise, Magali et al

Poster (2012, June)

Six variants of human lysozyme (single-point mutatants I56T, F57I, W64R, D67H and double mutants F57I/T70N, W112R/T70N) are associated with a hereditary non-neuropathic systemic amyloidosis. These ... [more ▼]

Six variants of human lysozyme (single-point mutatants I56T, F57I, W64R, D67H and double mutants F57I/T70N, W112R/T70N) are associated with a hereditary non-neuropathic systemic amyloidosis. These proteins form extracellular amyloid fibrils that deposit in a wide range of tissues and organs such as liver, spleen and kidneys where they cause damages [1]. It was shown that the D67H and I56T mutations cause a loss in stability and more particularly a loss of global cooperativity of protein [1]. Consequently, under physiologically relevant conditions, these variants can transiently populate a partially unfolded state in which the beta-domain and the C-helix are cooperatively unfolded while the rest of the protein remains native like [1]. The formation of intermolecular interactions between the regions that are unfolded in this intermediate state is likely to be a fundamental trigger of the aggregation process that ultimately leads to the formation and deposition of fibrils in tissues. We have also shown that the binding of three variable domain of camelid antibodies (VHHs) - raised against the wild type human lysozyme inhibit in vitro the formation of amyloid fibrils by the lysozyme variants. These three VHHs bind on different regions of lysozyme and act as amyloid fibril inhibitor through different mechanisms [2, 3, and unpublished results]. In the present work, sixteen new VHHs specific of human lysozyme have been generated. Competition experiments have shown that they bind to five non-overlapping epitopes. We have demonstrated that five of these VHHs are able to bind lysozyme in conditions used for amyloid fibril formation, and interestingly two of them recognize two epitopes that are different from those of the three VHHs previously characterized [2, 3, and unpublished results]. The effects of these new VHHs on the properties of lysozyme variants such as stability, cooperativity and aggregation will be discussed. [1] Dumoulin, M., J.R. Kumita, and C.M. Dobson, Normal and aberrant biological self-assembly: Insights from studies of human lysozyme and its amyloidogenic variants. Acc Chem Res, 2006, 39(9), 603-610. [2] Dumoulin, M., et al., A camelid antibody fragment inhibits the formation of amyloid fibrils by human lysozyme. Nature, 2003, 424, 783-788. [3] Chan, P.H., et al., Engineering a camelid antibody fragment that binds to the active site of human lysozyme and inhibits its conversion into amyloid fibrils. Biochemistry, 2008, 47, 11041-11054. [less ▲]

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See detailDisease-related amyloidogenic variants of human lysozyme trigger the unfolded protein response and disturb eye development in Drosophila melanogaster
Kumita, Janet R.; Helmfors, Linda; Williams, Jocy et al

in FASEB Journal (2012)

We have created a Drosophila model of lysozyme amyloidosis to investigate the in vivo behavior of disease-associated variants. To achieve this objective, wild-type (WT) protein and the amyloidogenic ... [more ▼]

We have created a Drosophila model of lysozyme amyloidosis to investigate the in vivo behavior of disease-associated variants. To achieve this objective, wild-type (WT) protein and the amyloidogenic variants F57I and D67H were expressed in Drosophila melanogaster using the UAS-gal4 system and both the ubiquitous and retinal expression drivers Act5C-gal4 and gmr-gal4. The nontransgenic w(1118) Drosophila line was used as a control throughout. We utilized ELISA experiments to probe lysozyme protein levels, scanning electron microscopy for eye phenotype classification, and immunohistochemistry to detect the unfolded protein response (UPR) activation. We observed that expressing the destabilized F57I and D67H lysozymes triggers UPR activation, resulting in degradation of these variants, whereas the WT lysozyme is secreted into the fly hemolymph. Indeed, the level of WT was up to 17 times more abundant than the variant proteins. In addition, the F57I variant gave rise to a significant disruption of the eye development, and this correlated to pronounced UPR activation. These results support the concept that the onset of familial amyloid disease is linked to an inability of the UPR to degrade completely the amyloidogenic lysozymes prior to secretion, resulting in secretion of these destabilized variants, thereby leading to deposition and associated organ damage.-Kumita, J. R., Helmfors, L., Williams, J., Luheshi, L. M., Menzer, L., Dumoulin, M., Lomas, D. A., Crowther, D. C., Dobson, C. M., Brorsson, A.-C. Disease-related amyloidogenic variants of human lysozyme trigger the unfolded protein response and disturb eye development in Drosophila melanogaster. [less ▲]

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See detailVHHs as structural probes to investigate the mechanis of fibril formation by the amyloidogenic variants of human lysozyme
Dumont, Janice; Kumita, Janet; Menzer, Linda et al

Scientific conference (2011, August 26)

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See detailVHHs as model proteins to investigate amyloid fibril formation: effect of seeding and cross-seeding on the stability of fibrils
Chavignon, Chloé ULg; Pardon, Els; Wyns, Lode et al

Poster (2011, August)

The term "amyloidosis" covers a group of diseases associated with the deposition of protein aggregates organized into amyloid fibrils in different organs. About forty amyloidoses are known so far, amongst ... [more ▼]

The term "amyloidosis" covers a group of diseases associated with the deposition of protein aggregates organized into amyloid fibrils in different organs. About forty amyloidoses are known so far, amongst which Alzheimer's disease, type II diabetes and immunoglobulin amyloidosis [1]. Although the mechanism of amyloid fibril formation at the molecular level is not yet completely understood, it has been shown that the capacity to form amyloid fibrils in vitro is an intrinsic property of all polypeptide chains [1]. The choice of model proteins to investigate the aggregation process in vitro is therefore not restrained to proteins involved in amyloidoses but can be settled on a wide variety of proteins. In this study, we have chosen to investigate the mechanism of amyloid fibril formation by two variable domains of camelid heavy-chain antibodies (referred to as VHHs or nanobodies), cAb-HuL6 and cAb-BcII10, for which variants with mutations located at the disulfide bond [3,4] and the CDRs [3] are available. Characterisation of the aggregating properties of these mutants will allow the investigation of the impact of these structural elements on the process of fibril formation. In order to determine conditions in which cAb-HuL6 and cAb-BcII10 are more susceptible to form amyloid fibrils, heat-induced unfolding experiments at several pHs have been monitored by intrinsic fluorescence and circular dichroism. Then, aggregation experiments have been performed in the selected conditions and the presence of amyloid fibrils has been acknowledged by thioflavineT fluorescence experiments and electron microscopy. We will discuss the kinetics of aggregation obtained in the absence and the presence of seeding/cross-seeding and the stability of the formed fibrils. [1] Chiti and Dobson, Annu. Rev. Biochem., 75, 2006, 333-366 ; [2] Dumoulin et al., Protein Sci., 11, 2002, 500-515 ; [3] Saerens et al., J. Mol. Biol., 352, 2005, 597-607 ; [4] Saerens et al., J. Mol. Biol., 377, 2008, 478-488. [less ▲]

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See detailMechanism of amyloid fibril formation by human lysozyme and VHHs
Dumoulin, Mireille ULg; Chavignon, Chloé ULg

Conference (2011, January)

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See detailEffects of monopropanediamino-beta-cyclodextrin on the denaturation process of the hybrid protein BlaPChBD.
Vandevenne, Marylène ULg; GASPARD, Genevieve ULg; Belgsir, E. M. et al

in Biochimica et biophysica acta (2011)

Irreversible accumulation of protein aggregates represents an important problem both in vivo and in vitro. The aggregation of proteins is of critical importance in a wide variety of biomedical situations ... [more ▼]

Irreversible accumulation of protein aggregates represents an important problem both in vivo and in vitro. The aggregation of proteins is of critical importance in a wide variety of biomedical situations, ranging from diseases (such as Alzheimer's and Parkinson's diseases) to the production (e.g. inclusion bodies), stability, storage and delivery of protein drugs. beta-Cyclodextrin (beta-CD) is a circular heptasaccharide characterized by a hydrophilic exterior and a hydrophobic interior ring structure. In this research, we studied the effects of a chemically modified beta-CD (BCD07056), on the aggregating and refolding properties of BlaPChBD, a hybrid protein obtained by inserting the chitin binding domain of the human macrophage chitotriosidase into the class A beta-lactamase BlaP from Bacillus licheniformis 749/I during its thermal denaturation. The results show that BCD07056 strongly increases the refolding yield of BlaPChBD after thermal denaturation and constitutes an excellent additive to stabilize the protein over time at room temperature. Our data suggest that BCD07056 acts early in the denaturation process by preventing the formation of an intermediate which leads to an aggregated state. Finally, the role of beta-CD derivatives on the stability of proteins is discussed. [less ▲]

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See detailNanobodies as structural probes to investigate the mechanism of fibril formation by the amyloidogenic variants of human lysozyme
Dumont, Janice ULg; Pardon, Els; Aumont-Nicaise, Magalie et al

Poster (2011)

Six variants of human lysozyme (single-point mutations I56T, F57I, W64R, D67H and double mutations F57I/T70N, W112R/T70N) are associated with a hereditary non-neuropathic systemic amyloidose. These ... [more ▼]

Six variants of human lysozyme (single-point mutations I56T, F57I, W64R, D67H and double mutations F57I/T70N, W112R/T70N) are associated with a hereditary non-neuropathic systemic amyloidose. These proteins form extracellular amyloid fibrils that deposit in a wide range of tissues and organs such as liver, spleen and kidneys where they cause damages [1]. It was shown that the D67H and I56T mutations cause a loss in stability and more particularly a loss of global cooperativity of protein [1]. Consequently, under physiologically relevant conditions, these variants can transiently populate a partially unfolded state in which the beta-domain and the C-helix are cooperatively unfolded while the rest of the protein remains native like [1]. The formation of intermolecular interactions between the regions that are unfolded in this intermediate state is likely to be a fundamental trigger of the aggregation process that ultimately leads to the formation and deposition of fibrils in tissues. We have also shown that the binding of three variable domain of camelid antibodies or (VHHs) - raised against the wild type human lysozyme inhibit in vitro the formation of amyloid fibrils by the lysozyme variants. These three VHHs bind on different regions of lysozyme and act as amyloid fibrils inhibitor through different mechanisms [2, 3, and unpublished results]. In the present work, sixteen new VHHs specific of human lysozyme have been generated. Competition experiments have shown that they bind to five non overlapping epitopes. We have demonstrated that five of these new VHHs are able to bind lysozyme in conditions used for amyloid fibril formation, and interestingly two of them recognize two epitopes that are different from those of the three VHHs previously characterized [2, 3, and unpublished results]. The effects of these new VHHs on the properties of lysozyme variants such as activity, stability, cooperativity and aggregation will be discussed. [less ▲]

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See detailPopulation of nonnative States of lysozyme variants drives amyloid fibril formation.
Buell, Alexander K.; Dhulesia, Anne; Mossuto, Maria F. et al

in Journal of the American Chemical Society (2011), 133(20), 7737-43

The propensity of protein molecules to self-assemble into highly ordered, fibrillar aggregates lies at the heart of understanding many disorders ranging from Alzheimer's disease to systemic lysozyme ... [more ▼]

The propensity of protein molecules to self-assemble into highly ordered, fibrillar aggregates lies at the heart of understanding many disorders ranging from Alzheimer's disease to systemic lysozyme amyloidosis. In this paper we use highly accurate kinetic measurements of amyloid fibril growth in combination with spectroscopic tools to quantify the effect of modifications in solution conditions and in the amino acid sequence of human lysozyme on its propensity to form amyloid fibrils under acidic conditions. We elucidate and quantify the correlation between the rate of amyloid growth and the population of nonnative states, and we show that changes in amyloidogenicity are almost entirely due to alterations in the stability of the native state, while other regions of the global free-energy surface remain largely unmodified. These results provide insight into the complex dynamics of a macromolecule on a multidimensional energy landscape and point the way for a better understanding of amyloid diseases. [less ▲]

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See detailDisulfide Bonds Reduce the Toxicity of the Amyloid Fibrils Formed by an Extracellular Protein.
Mossuto, M. F.; Bolognesi, B.; Guixer, B. et al

in Angewandte Chemie (International ed. in English) (2011)

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