Protein-to-lipid ratio uniquely changes the rate of lysozyme aggregation but does not significantly alter toxicity of mature protein aggregates

Zhaliazka, Kiryl; Serada, Valeryia; Matveyenka, Mikhail; Rizevsky, Stanislav; Kurouski, Dmitry

doi:10.1016/j.bbalip.2023.159305

Cited by 6 publications

(7 citation statements)

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“…However, an increase in the concentration of PS relative to the concentration of lysozyme to 1:5 and 1:10 resulted in a drastic increase in the rate of protein aggregation. (Zhaliazka, Serada, et al, 2023b) Furthermore, it was found that lipids not only altered the rates of protein aggregation, but uniquely modified the morphology and secondary structure of protein aggregates formed in their presence (Matveyenka et al, 2023; Matveyenka, Rizevsky, & Kurouski, 2022a; Matveyenka, Rizevsky, & Kurouski, 2022b; Matveyenka, Rizevsky, & Kurouski, 2022c; Matveyenka, Rizevsky, & Kurouski, 2022d; Matveyenka, Zhaliazka, et al, 2022). Experimental results reported by Dou et al suggested that lipids could temper protein aggregation (Dou et al, 2021; Dou & Kurouski, 2022).…”

Section: Introductionmentioning

confidence: 99%

Length and saturation of fatty acids in phosphatidylserine determine the rate of lysozyme aggregation simultaneously altering the structure and toxicity of amyloid oligomers and fibrils

et al. 2023

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Abrupt aggregation of misfolded proteins is the underlying molecular cause of numerous severe pathologies including Alzheimer's and Parkinson's diseases.Protein aggregation yields small oligomers that can later propagate into amyloid fibrils, β-sheet-rich structures with a variety of topologies. A growing body of evidence suggests that lipids play an important role in abrupt aggregation of misfolded proteins. In this study, we investigate the roles of length and saturation of fatty acids (FAs) in phosphatidylserine (PS), an anionic lipid that is responsible for the recognition of apoptotic cells by macrophages, in lysozyme aggregation. We found that both the length and saturation of FAs in PS contribute to the aggregation rate of insulin. PS with 14-carbon-long FAs (14:0) enabled a much stronger acceleration of protein aggregation compared to PS with 18-carbon-long FAs (18:0). Our results demonstrate that the presence of double bonds in FAs accelerated the rate of insulin aggregation relative to PS with fully saturated FAs. Biophysical methods revealed morphological and structural differences in lysozyme aggregates grown in the presence of PS with varying lengths and FA saturation. We also found that such aggregates exerted diverse cell toxicities. These results demonstrate that the length and saturation of FAs in PS can uniquely alter the stability of misfolded proteins on lipid membranes.

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Section: Introductionmentioning

confidence: 99%

Length and saturation of fatty acids in phosphatidylserine determine the rate of lysozyme aggregation simultaneously altering the structure and toxicity of amyloid oligomers and fibrils

et al. 2023

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“…Experimental results reported by our group and other research groups demonstrated that lipids uniquely altered the morphology and secondary structure of amyloid aggregates formed in their presence. ,,− ,, Specifically, both insulin and lysozyme formed spherical oligomers in the presence of PC and PE. , These aggregates dominated by unordered protein secondary structure possessing very few if any β-sheets. At the same time, insulin and lysozyme formed fibrils in the presence of negatively charged lipids, such as CL, PS, and PG. , These aggregates were dominated by a parallel β-sheet secondary structure.…”

Section: Structural Organization Of Amyloid Oligomers and Fibrilsmentioning

confidence: 68%

“…It should be noted that both insulin and lysozyme aggregates formed in the presence of lipids possessed corresponding lipids in their structure. ,,− ,, Similar results were reported by Zhaliazka and co-workers for Aβ 1–42 oligomers and fibrils formed in the presence of CL, PC, and the PC:cholesterol mixture . It was found that Aβ 1–42 aggregates exhibit a vibrational band centered at around 1730 cm –1 , which could be assigned to the CO vibration of lipids from the AFM-IR spectra acquired from these species.…”

Section: Structural Organization Of Amyloid Oligomers and Fibrilsmentioning

confidence: 95%

“…Based on these results, we could conclude that the rate of protein aggregation directly depends on the net charge of the lipid. Zhaliazka and co-workers discovered that the enhancement rate of protein aggregation directly depends not only on the chemical structure of the lipid, but also on the P:L ratio . Specifically, PS and CL exhibited a much stronger enhancement of lysozyme aggregation if they were present at 1:10 and 1:5 compared to 1:1 P:L ratios.…”

Section: Structural Organization Of Amyloid Oligomers and Fibrilsmentioning

confidence: 99%

“…Experimental results reported by our group and other research groups demonstrated that lipids uniquely altered the morphology and secondary structure of amyloid aggregates formed in their presence. 2,3,[30][31][32][33][34][35][36][37][38]44,45 Specifically, both insulin and lysozyme formed spherical oligomers in the presence of PC and PE. 37,44 These aggregates dominated by unordered protein secondary structure possessing very few if any β-sheets.…”

Section: Structure and Morphology Of Amyloid Aggregates Formed In The...mentioning

confidence: 99%

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Elucidating the Role of Lipids in the Aggregation of Amyloidogenic Proteins

Kurouski

2023

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS:The abrupt aggregation of misfolded proteins is linked to the onset and spread of amyloidogenic diseases, including diabetes type 2, systemic amyloidosis, and Alzheimer's (AD) and Parkinson's diseases (PD). Although the exact cause of these pathological processes is unknown, a growing body of evidence suggests that amyloid diseases are triggered by misfolded or unfolded proteins, forming highly toxic oligomers. These transient species exhibit high structural and morphological heterogeneity. Protein oligomers can also propagate into β-sheet-rich filaments that braid and coil with other filaments to form amyloid fibrils and supramolecular structures with both flat and twisted morphologies. Microscopic examination of protein deposits formed in the brains of both AD and PD patients revealed the presence of fragments of lipid membranes. Furthermore, nanoscale infrared analysis of ex vivo extracted fibrils revealed the presence of lipids in their structure (Zhaliazka, K.; Kurouski, D.Protein Sci. 2023, 32, e4598). These findings demonstrated that lipid bilayers could play an important role in the aggregation of misfolded proteins. Experimental findings summarized in this Account show that (i) lipids uniquely change the aggregation rate of amyloidogenic proteins. In this case, the observed changes in the rates directly depend on the net charge of the lipid and the length and saturation of lipid fatty acids (FAs). For instance, zwitterionic phosphatidylcholine (PC) with 14:0 FAs inhibited the aggregation of insulin, lysozyme, and α-synuclein (α-Syn), whereas anionic phosphatidylserine with the same FAs dramatically accelerated the aggregation rate of these proteins (Dou, T., et al.

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Exploring the thermodynamics of protein aggregation: an insight to Huntington's disease therapeutics

Kaundal,

Pandey,

Pandey

2024

Neurosci Behav Physi

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Protein-to-lipid ratio uniquely changes the rate of lysozyme aggregation but does not significantly alter toxicity of mature protein aggregates

Cited by 6 publications

References 51 publications

Length and saturation of fatty acids in phosphatidylserine determine the rate of lysozyme aggregation simultaneously altering the structure and toxicity of amyloid oligomers and fibrils

Length and saturation of fatty acids in phosphatidylserine determine the rate of lysozyme aggregation simultaneously altering the structure and toxicity of amyloid oligomers and fibrils

Elucidating the Role of Lipids in the Aggregation of Amyloidogenic Proteins

Exploring the thermodynamics of protein aggregation: an insight to Huntington's disease therapeutics

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