Kinetics theories to understand the mechanism of aggregation of a protein and to design strategies for its inhibition

Sharma, Shilpa; Modi, Priya; Sharma, Gargi; Deep, Shashank

doi:10.1016/j.bpc.2021.106665

Cited by 35 publications

(20 citation statements)

References 176 publications

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“…Our research provides a new biophysical tool for investigating the oligomerization and aggregation of SOD1. , First, our work shows that the corkscrew-like intermediate is an early-on on-pathway species and can stabilize for a period of time. Thus, using the same approach, we can investigate how this corkscrew-like intermediate interacts with the cell membranes from the perspective of the Trp side chains and the backbones, providing a molecular picture to understand the toxicity of the intermediate.…”

Section: Resultsmentioning

confidence: 85%

Probing Intermolecular Interactions of Amyloidogenic Fragments of SOD1 by Site-Specific Tryptophan and Its Noncanonical Derivative

et al. 2021

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Transient amyloid intermediates are likely to be cytotoxic and play an essential role in amyloid-associated neurodegenerative diseases. Characterization of their structural and dynamic evolution is the key to elucidating the molecular mechanism of amyloid formation. Here, combining circular dichroism (CD), exciton couplet theory, and Fourier transform infrared spectroscopy with site-specific tryptophan (Trp) and its noncanonical derivative 5-cyano-tryptochan (Trp 5CN ), we developed a method to monitor strand-to-strand tertiary and sheet-tosheet quaternary interactions in the aggregation cascades of an amyloidogenic fragment from protein SOD1 28−38 (with the sequence KVKVWGSIKGL). We found that the exciton couplet generated from the B b band of Trp can be used as a probe for side chain interactions. Its sensitivity can be further improved by four times with the incorporation of Trp 5CN . We further observed a red-shift of ∼2 cm −1 and a broadening of ∼2 cm −1 in the IR band generated from the CN stretch during the aggregation, which we attributed to the transition from a corkscrew-like structure to a cross-linked intermediate phase. We show here that the integration of optical methods with unique aromatic side chain-related probes is able to elucidate amyloid intermolecular interactions and even capture elusive transient intermediates on and off the amyloid assembling pathway.

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Section: Resultsmentioning

confidence: 85%

Probing Intermolecular Interactions of Amyloidogenic Fragments of SOD1 by Site-Specific Tryptophan and Its Noncanonical Derivative

et al. 2021

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“… 5–8 Knowledge about their structures and assembly pathways is crucial for understanding Aβ oligomerization mechanisms, the molecular basis of AβO toxicity, and its interplay with other aggregation diseases, 9 based on which aggregation inhibition strategies may be designed. 10,11 There are two major Aβ alloforms that contain 40 and 42 amino acids, respectively. Aβ42, which has two more amino acids at the C-terminus, oligomerizes more easily and is more neurotoxic.…”

Section: Introductionmentioning

confidence: 99%

Anatomy and formation mechanisms of early amyloid-β oligomers with lateral branching: graph network analysis on large-scale simulations

2022

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“…In particular, the structural intermediates evolving during the aggregation process which have been assessed as being the key malign species are highly transient and diversified rendering them a scientific subject that features even more obscurity and necessitates further investigation and research. Any structural information about the Aβ peptide conversion into oligomers and finally fibrils is considered crucial for developing new strategies for tackling AD [ 3 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Probing the Influence of Single-Site Mutations in the Central Cross-β Region of Amyloid β (1–40) Peptides

et al. 2021

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Amyloid β (Aβ) is a peptide known to form amyloid fibrils in the brain of patients suffering from Alzheimer’s disease. A complete mechanistic understanding how Aβ peptides form neurotoxic assemblies and how they kill neurons has not yet been achieved. Previous analysis of various Aβ40 mutants could reveal the significant importance of the hydrophobic contact between the residues Phe19 and Leu34 for cell toxicity. For some mutations at Phe19, toxicity was completely abolished. In the current study, we assessed if perturbations introduced by mutations in the direct proximity of the Phe19/Leu34 contact would have similar relevance for the fibrillation kinetics, structure, dynamics and toxicity of the Aβ assemblies. To this end, we rationally modified positions Phe20 or Gly33. A small library of Aβ40 peptides with Phe20 mutated to Lys, Tyr or the non-proteinogenic cyclohexylalanine (Cha) or Gly33 mutated to Ala was synthesized. We used electron microscopy, circular dichroism, X-ray diffraction, solid-state NMR spectroscopy, ThT fluorescence and MTT cell toxicity assays to comprehensively investigate the physicochemical properties of the Aβ fibrils formed by the modified peptides as well as toxicity to a neuronal cell line. Single mutations of either Phe20 or Gly33 led to relatively drastic alterations in the Aβ fibrillation kinetics but left the global, as well as the local structure, of the fibrils largely unchanged. Furthermore, the introduced perturbations caused a severe decrease or loss of cell toxicity compared to wildtype Aβ40. We suggest that perturbations at position Phe20 and Gly33 affect the fibrillation pathway of Aβ40 and, thereby, influence the especially toxic oligomeric species manifesting so that the region around the Phe19/Leu34 hydrophobic contact provides a promising site for the design of small molecules interfering with the Aβ fibrillation pathway.

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Kinetics theories to understand the mechanism of aggregation of a protein and to design strategies for its inhibition

Cited by 35 publications

References 176 publications

Probing Intermolecular Interactions of Amyloidogenic Fragments of SOD1 by Site-Specific Tryptophan and Its Noncanonical Derivative

Probing Intermolecular Interactions of Amyloidogenic Fragments of SOD1 by Site-Specific Tryptophan and Its Noncanonical Derivative

Anatomy and formation mechanisms of early amyloid-β oligomers with lateral branching: graph network analysis on large-scale simulations

Probing the Influence of Single-Site Mutations in the Central Cross-β Region of Amyloid β (1–40) Peptides

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