Protein folding, misfolding and aggregation: A tale of constructive to destructive assembly

Khan, Rizwan Hasan; Zakariya, Syed Mohammad; Khan, Rizwan Hasan

doi:10.1016/j.ijbiomac.2018.01.099

Cited by 22 publications

(5 citation statements)

References 190 publications

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“…Gain of toxicity and/or loss of function can lead to: -Neurodegeneration (Ross et al, Aguzzi et al 2010) -Systemic amyloidosis ( Features characterizing protein aggregates. Physiological and pathological protein aggregates are very diverse and multifaceted, and may be categorized based on features like structure [5,8,9,13,15,21,22,38,44], function [1,2,5,8,9,12,13,[23][24][25][26][44][45][46], reversibility [5][6][7][8][9], infectivity [27][28][29][30][31], localization [5,8,15,[32][33][34]47] and composition [5,35,36].…”

Section: Pathological Aggregatesmentioning

confidence: 99%

Reversible, functional amyloids: towards an understanding of their regulation in yeast and humans

et al. 2018

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Protein aggregates, and in particular amyloids, are generally considered to be inherently irreversible aberrant clumps, and are often associated with pathologies, such as Alzheimer's disease, Parkinson's disease, or systemic amyloidosis. However, recent evidence demonstrates that some aggregates are not only fully reversible, but also perform essential physiological functions. Despite these new findings, very little is known about how these functional protein aggregates are regulated in a physiological context. Here, we take the yeast pyruvate kinase Cdc19 as an example of a protein forming functional, reversible, solid, amyloid-like aggregates in response to stress conditions. Cdc19 aggregation is regulated via an aggregation-prone low complexity region (LCR). In favorable growth conditions, this LCR is prevented from aggregating by phosphorylation or oligomerization, while upon glucose starvation it becomes exposed and allows aggregation. We suggest that LCR phosphorylation, oligomerization or partner-binding may be general and widespread mechanisms regulating LCR-mediated reversible protein aggregation. Moreover, we show that, as predicted by computational tools, Cdc19 forms amyloid-like aggregates in vitro. Interestingly, we also observe striking similarities between Cdc19 and its mammalian counterpart, PKM2. Indeed, also PKM2 harbors a LCR and contains several peptides with high amyloidogenic propensity, which coincide with known phosphorylation sites. Thus, we speculate that the formation of reversible, amyloid-like aggregates may be a general physiological mechanism for cells to adapt to stress conditions, and that the underlying regulatory mechanisms may be conserved from yeast to humans.

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Section: Pathological Aggregatesmentioning

confidence: 99%

Reversible, functional amyloids: towards an understanding of their regulation in yeast and humans

et al. 2018

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“…Storage of the protein solutions (with concentration ~ 1.5–3 μg/μL) at a room temperature results in a rather rapid transformation of MLPs into flexible worm‐like fibrils (Figure 2c–e). Such fibrils, sometimes referred to as elongated cylindrical micelles (Jacoby et al, 2021) or protofibrils (Eftekharzadeh et al, 2016; Harper et al, 1997; Khan et al, 2018; Modler et al, 2004; Relini et al, 2010), were described for a number of amyloidogenic proteins (Eftekharzadeh et al, 2016; Gosal et al, 2005; Lomakin et al, 1996). They are considered as the precursors of more rigid amyloid structures (Conway et al, 2000; Dalal et al, 2015; Harper et al, 1997) or the off‐pathway by‐products (Caughey & Lansbury, 2003; Gosal et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Protein aggregation is a widespread phenomenon in living systems (Chiti & Dobson, 2017; Khan et al, 2018). The self‐assembly of proteins into highly structured fibrillar aggregates (amyloids) is associated with various currently incurable diseases, that is, Alzheimer's and Parkinson's diseases, type 2 diabetes, prion diseases, and so forth (see for review Chiti & Dobson, 2017; Eftekharzadeh et al, 2016; Ke et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Atomic force microscopy of spherical intermediates on the pathway to fibril formation of influenza A virus nuclear export protein

Koroleva,

Kuzmina,

Dubrovin

et al. 2024

Microscopy Res & Technique

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The nuclear export protein of the influenza A virus (NEP) is involved in many important processes of the virus life cycle. This makes it an attractive target for the treatment of a disease caused by a virus. Previously it has been shown, that recombinant variants of NEP are highly prone to aggregation in solution under various conditions with the formation of amyloid‐like aggregates. In the present work, the amyloid nature of NEP aggregates was evidenced by Congo red binding assays. Atomic force microscopy has shown that NEP can form two types of spherical nanoparticles, which provide an alternative pathway for the formation of amyloid‐like fibrils. Type I of these “fibrillogenic” spheres, formed under physiological conditions, represents the micelle‐like particles with height 10–60 nm, which can generate worm‐like flexible fibrils with the diameter 2.5–4.0 nm, length 20–500 nm and the Young's modulus ~73 MPa. Type II spherical aggregates with size of about 400–1000 nm, formed at elevated temperatures, includes fractions of drop‐like and vesicle‐like particles, generating more rigid amyloid‐like fibrils with height of ~8 nm, and length of up to 2 μm. The hypothetical mechanism of fibril formation via nanospherical structures was suggested.Research Highlights AFM has revealed two types of the influenza A virus nuclear export protein spherical aggregates. They provide an alternative pathway for the formation of amyloid‐like fibrils. The mechanism of fibril formation via spherical structures is suggested.

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“…During the upcoming growth phase, the oligomers grow rapidly into protofibrils that form fibers and further extensive amyloid aggregates at the saturation phase. 62,63 The time-scale for the course of these events varies a lot being different for in vitro and in vivo processes and for different precursor proteins.…”

Section: Protein Misfolding and Amyloid Diseasementioning

confidence: 99%

Multimodal Porphyrin-Based Conjugates: Synthesis and characterization for applications as amyloid ligands, photodynamic therapy agents and chiroptical materials

Arja¹

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Organic compounds that interact both with certain biological targets and display specific photophysical properties can be utilized as molecular tools to visualize and possibly affect disease related processes taking place in living organisms. In this regard, porphyrins are a class of naturally occurring molecules that possess intriguingly interesting photophysical properties where they can act as luminescent probes by emitting detectable light, as well as photosensitizers in the light mediated therapy denoted photodynamic therapy. In this thesis, the porphyrin structure has been synthetically combined with other types of molecules to achieve compounds with desirable multimodal characteristics. During my doctoral studies at Chemistry department at Linköping university, several people have contributed to the scientific work that I carried out, helped me with the everyday matters or supported me in general. I would like to thank all these fantastic people and especially acknowledge some of them: Professor Peter Nilsson, my supervisor, for all the guidance and support through the years. You are an expert on helping me see the possibilities in seemingly tiny things that would eventually lead to fascinating research projects. Professor Peter Konradsson, my co-supervisor, for the help in navigating in the world of organic chemistry and for the all the philosophical discussions about the rest of the world. All the past and present members of the Nilsson group: Therése for always being the wise and calm ideal of a researcher; Hamid with his never-disturbed and inspiring enthusiasm in synthetic chemistry; the chatty and positive Bisse for all her advice on chemistry and life, and for all the enjoyable coffee breaks and lunches; Elisabet for being one of the few downright good people left in this world and surely one of the persons with the highest number of different interests; Hanna for the fruitful collaborations and pleasant company; Karin, Rozalyn, Leffe, Jeff, Andreas, Timmy and Mikaela for all the help and for all the memorable moments at works. Mathias Elgland, another downright good person with a plethora of positive qualities ranging from being an excellent chemist to a worthy friend. I am deeply grateful for all the scientific collaborations and the friendship along the side. Thank you for your most enjoyable company over my many years at Linköping university! Linda Lantz, my roomie and a dear colleague and a friend, for cheering my days with interesting scientific and even more interesting non-scientific talk. You inspire with you strong and independent angles of life philosophy. Marcus Bäck, for being a truly understanding and reliable friend and a helpful colleague, and for backing me up with "Det gör du rätt i". Jakob Wallgren for m/baking my days with all these splendid pastries and with your pleasant company! People in Organic chemistry corridor: Xiongyu Wu, a true sensei in chemistry; Yun, Tobias, Roger.

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Protein folding, misfolding and aggregation: A tale of constructive to destructive assembly

Cited by 22 publications

References 190 publications

Reversible, functional amyloids: towards an understanding of their regulation in yeast and humans

Reversible, functional amyloids: towards an understanding of their regulation in yeast and humans

Atomic force microscopy of spherical intermediates on the pathway to fibril formation of influenza A virus nuclear export protein

Multimodal Porphyrin-Based Conjugates: Synthesis and characterization for applications as amyloid ligands, photodynamic therapy agents and chiroptical materials

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