Conformational Differences between Two Amyloid β Oligomers of Similar Size and Dissimilar Toxicity

Ladiwala, Ali Reza A.; Litt, Jeffrey; Kane, Ravi S.; Aucoin, Darryl; Smith, Steven O.; Ranjan, Swarnim; Davis, James Earl; Nostrand, William E. Van; Tessier, Peter M.

doi:10.1074/jbc.m111.329763

Cited by 199 publications

(299 citation statements)

References 37 publications

Supporting

Mentioning

275

Contrasting

Order By: Relevance

“…Similar behaviour has been observed for -synuclein (Chen et al 2015). (Oma et al, 2005;Bolognesi et al, 2010;Olzscha et al, 2011;Ladiwala et al, 2012). This has also been observed for HypF-N oligomers (Campioni et al, 2010;Bemporad and Chiti, 2012).…”

Section: Resultssupporting

confidence: 63%

Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations

Cappelli

Penco²,

Mannini³

et al. 2016

Biological Chemistry

View full text Add to dashboard Cite

. (2016). Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations. Biological Chemistry: official scientific journal of the GBM, 397 (5), 401-415. Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations AbstractLiving systems protect themselves from aberrant proteins by a network of chaperones. We have tested in vitro the effects of different concentrations, ranging from 0 to 16 μm, of two molecular chaperones, namely αB-crystallin and clusterin, and an engineered monomeric variant of transthyretin (M-TTR), on the morphology and cytotoxicity of preformed toxic oligomers of HypF-N, which represent a useful model of misfolded protein aggregates. Using atomic force microscopy imaging and static light scattering analysis, all were found to bind HypF-N oligomers and increase the size of the aggregates, to an extent that correlates with chaperone concentration. SDS-PAGE profiles have shown that the large aggregates were predominantly composed of the HypF-N protein. ANS fluorescence measurements show that the chaperone-induced clustering of HypF-N oligomers does not change the overall solvent exposure of hydrophobic residues on the surface of the oligomers. αB-crystallin, clusterin and M-TTR can diminish the cytotoxic effects of the HypF-N oligomers at all chaperone concentration, as demonstrated by MTT reduction and Ca2+ influx measurements. The observation that the protective effect is primarily at all concentrations of chaperones, both when the increase in HypF-N aggregate size is minimal and large, emphasizes the efficiency and versatility of these protein molecules. Disciplines Medicine and Health Sciences | Social and Behavioral Sciences Publication DetailsCappelli, S., Penco, A., Mannini, B., Cascella, R., Wilson, M. R., Ecroyd, H., Li, X., Buxbaum, J. N., Dobson, C. M., Cecchi, C., Relini, A. & Chiti, F. (2016 measurements. The observation that the protective effect is primarily at all concentrations of chaperones, both when the increase in HypF-N aggregate size is minimal and large, emphasises the efficiency and versatility of these protein molecules.

show abstract

Section: Resultssupporting

confidence: 63%

Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations

Cappelli

Penco²,

Mannini³

et al. 2016

Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…We used antibodies specific for prefibrillar oligomers (A11) and fibrillar conformers (OC) to monitor the aggregation of Aβ42 via immunoblotting ( Fig. 2A), as we reported previously (4,10). In the absence of gammabody inhibitors, Aβ forms prefibrillar oligomers (recognized by the A11 antibody) after 1 d; these oligomers convert into fibrillar conformers (recognized by the OC antibody) on the second day and persist for an additional 4 d (longer times not evaluated).…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, we evaluated the impact of the Aβ12-21 and Aβ33-42 gammabodies on the relative solvent accessibility of N-terminal (Aβ residues 3-10), middle (Aβ residues [18][19][20][21][22], and C-terminal (Aβ residues 30-36) Aβ peptide segments during fibrillization using a proteolytic assay that we have reported previously (10). We find that the solvent accessibility of the hydrophilic N terminus of Aβ is unchanged during Aβ fibrillization (days 0-6), and that the Aβ12-21 and Aβ33-42 gammabodies do not alter its solvent accessibility (Fig.…”

Section: Resultsmentioning

confidence: 99%

Rational design of potent domain antibody inhibitors of amyloid fibril assembly

Ladiwala

Bhattacharya

Perchiacca

et al. 2012

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

Self Cite

View full text Add to dashboard Cite

Fig. 7. IAPP and α-Synuclein gammabodies potently inhibit amyloid formation in a sequence-specific manner. IAPP (32 μM) and α-Synuclein (residues 1-115, 50 μM) were incubated in the absence (control) and presence of gammabodies (1:10 gammabody:monomer molar ratio), and fibrillization was monitored via (A) immunoblotting and (B) AFM. In B, IAPP and α-Synuclein fibrillization was also monitored in the presence of sequence-specific (R10/99, IAPP residues 7-17; 5C2, α-Synuclein residues 61-95) and conformation-specific (A11, prefibrillar oligomers; OC, fibrillar conformers) antibodies (1:10 antibody:monomer molar ratio). In B, the AFM images are 3 × 3 μm, and the blank images are samples with heights <1 nm. The heights of the IAPP and α-Synuclein aggregates are 21 ± 3 and 25 ± 4 nm, respectively.

show abstract

“…Planar Lipid Bilayer Experiments-Asolectin (Avanti Polar Lipids Inc.) bilayers were made by dissolving in n-decane at a concentration of 200 mg/ml (13,14) and formed over a polystyrene cup with a 100-m-diameter aperture and inserted into a thermally conductive chamber. The cup and the chamber were filled with 1 ml of 20 mM HEPES buffer (100 mM KCl, pH 7.4).…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, we decided to probe whether the long-lived SAA1.1 oligomers could disrupt model membranes in vitro. Asolectin bilayers are good mimics of biological membranes (14,24). Hence, we used them to screen for the ability of various SAA aggregates to destabilize or permeabilize lipid bilayers.…”

Section: Cross-seeding Experiments Suggest That Saa11 and Saa22 Formentioning

confidence: 99%

Pathogenic Serum Amyloid A 1.1 Shows a Long Oligomer-rich Fibrillation Lag Phase Contrary to the Highly Amyloidogenic Non-pathogenic SAA2.2

Srinivasan

Patke

Wang

et al. 2013

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: Murine SAA1.1 is pathogenic and SAA2.2 is non-pathogenic in AA amyloidosis. Results: SAA1.1 and SAA2.2 exhibit different biophysical properties, including fibrillation kinetics and fibril morphology. Conclusion:The distinct biophysical properties of highly homologous SAA proteins may contribute to their different pathogenicity during chronic inflammation. Significance: Structural and kinetic factors, more than their intrinsic amyloidogenicity, may determine the diverse pathogenicity among nearly identical SAA isoforms.

show abstract

Conformational Differences between Two Amyloid β Oligomers of Similar Size and Dissimilar Toxicity

Cited by 199 publications

References 37 publications

Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations

Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations

Rational design of potent domain antibody inhibitors of amyloid fibril assembly

Pathogenic Serum Amyloid A 1.1 Shows a Long Oligomer-rich Fibrillation Lag Phase Contrary to the Highly Amyloidogenic Non-pathogenic SAA2.2

Contact Info

Product

Resources

About