Molecular insights into the phase transition of lysozyme into amyloid nanostructures: Implications of therapeutic strategies in diverse pathological conditions

Roy, Sindhujit; Srinivasan, Venkat Ramanan; Arunagiri, Subash; Mishra, Nishant; Bhatia, Anubhuti; Shejale, Kiran P.; Prajapati, Kailash Prasad; Kar, Karunakar; Anand, Bibin Gnanadhason

doi:10.1016/j.cis.2024.103205

Cited by 2 publications

(2 citation statements)

References 210 publications

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“…As can be established by testing various sequences on the above servers (we focused on AmyloGram [74,96], see later), as well as the classical amyloidoses, a very great many [120][121][122] (and possibly most [123]) proteins can exhibit amyloid formation under certain conditions [65,124]. Examples include insulin [125][126][127], lysozyme [128][129][130][131][132][133][134][135][136], proteins providing structure/texture in various processed foods and other gels [137-139], and even certain yeast [140][141][142] and bacterial [143] proteins, including some that can be 'inherited'.…”

Section: Prevalence Of Amyloidogenicitymentioning

confidence: 99%

Proteomic evidence for amyloidogenic cross-seeding in fibrinaloid microclots

Kell,

Pretorius

2024

Preprint

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In classical amyloidoses, amyloid fibres form through the nucleation and accretion of protein monomers, with protofibrils and fibrils exhibiting a cross-β motif of parallel or antiparallel β-sheets oriented perpendicular to the fibre direction. These protofibrils and fibrils can intertwine to form mature amyloid fibres. Similar phenomena occur in blood from individuals with circulating inflammatory molecules (also those originating from viruses and bacteria). In the presence of inflammagens, pathological clotting can occur, that results in an anomalous amyloid form termed fibrinaloid microclots. Previous proteomic analyses of these microclots have shown the presence of non-fibrin(ogen) proteins, suggesting a more complex mechanism than simple entrapment. We provide evidence against a simple entrapment model, noting that clot pores are too large and centrifugation would have removed weakly bound proteins. Instead, we explore whether co-aggregation into amyloid fibres may involve axial (multiple proteins within the same fibril), lateral (single-protein fibrils contributing to a fibre), or both types of integration. Our analysis of proteomic data from fibrinaloid microclots in different diseases shows no significant overlap with the normal plasma proteome and no correlation between plasma protein abundance and presence in microclots. Notably, abundant plasma proteins like α-2-macroglobulin, fibronectin, and transthyretin are absent from microclots, while less abundant proteins such as adiponectin, periostin, and von Willebrand Factor are well represented. Using bioinformatic tools including AmyloGram and AnuPP, we found that proteins entrapped in fibrinaloid microclots exhibit high amyloidogenic tendencies, suggesting their integration as cross-β elements into amyloid structures. This integration likely contributes to the microclots’ resistance to proteolysis. Our findings underscore the role of cross-seeding in fibrinaloid microclot formation and highlight the need for further investigation into their structural properties and implications in thrombotic and amyloid diseases. These insights provide a foundation for developing novel diagnostic and therapeutic strategies targeting amyloidogenic cross-seeding in blood clotting disorders.

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Section: Prevalence Of Amyloidogenicitymentioning

confidence: 99%

Proteomic evidence for amyloidogenic cross-seeding in fibrinaloid microclots

Kell,

Pretorius

2024

Preprint

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“…Such energy level was comparatively more significant when compared to the interaction energies obtained for phytochemicals like eugenol, morin, stigmasterol, limonene, rosmarinic acid, and quercetin, which have a binding affinity of −5.89, −7.15, −7.29, −5.89, −7.17, and −7.78 kcal/ mol, respectively. 27 As the simulation progresses, the increased binding affinity of these 6-gingerol-derived semisynthetic analogues at the exposed hydrophobic core suggests their potential to inhibit other nonnative or native proteins from binding at these sites, thus delaying further aggregation, as shown in Figure 3A. Specifically, these compounds demonstrate a higher level of affinity when compared to their interaction with the equilibrated structure.…”

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confidence: 99%

Tailoring the Molecular Structure of 6-Gingerol for Targeting the Phase Separation in Human Lysozyme

Bonda,

Mishra,

Bhatia

et al. 2024

J. Phys. Chem. Lett.

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Human lysozyme undergoes a phase-separation process to form insoluble amyloid-architects that cause several pathologies including systemic amyloidosis. Here we have tailored 6gingerol by extending its molecular framework with active functional groups to specifically target lysozyme phase-transition events. Aggregation assay revealed that tailored 6-gingerol with 4-aromatic moieties (MTV4) substantially suppressed the conversion of the lysozyme low-density liquid phase (LDLP) to solid-phase structured amyloids. The data obtained from biophysical, computational, and microscopic imaging tools suggest direct intervention of MTV4 with the liquid−liquid phase separation. The CD data suggest that MTV4 was able to retain the native conformation of lysozyme. Both biomolecular and computational data reveal the interference of MTV4 with the aggregation-prone hydrophobic stretches within the lysozyme, thereby retaining the native structure and reversing the misfolded intermediates to active monomers. Also, MTV4 was able to induce rapid dissolution of preformed-toxic amyloid fibrils. These results reinforce the importance of the aromatic−aromatic interaction in preventing human lysozyme phase separation.

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Molecular insights into the phase transition of lysozyme into amyloid nanostructures: Implications of therapeutic strategies in diverse pathological conditions

Cited by 2 publications

References 210 publications

Proteomic evidence for amyloidogenic cross-seeding in fibrinaloid microclots

Proteomic evidence for amyloidogenic cross-seeding in fibrinaloid microclots

Tailoring the Molecular Structure of 6-Gingerol for Targeting the Phase Separation in Human Lysozyme

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