Functional amyloids in the human body

Brown, Amy; Török, Marianna

doi:10.1016/j.bmcl.2021.127914

Cited by 9 publications

(9 citation statements)

References 82 publications

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“…2D). Even very large Core WT amyloid aggregates tens of μm in diameter dissolved with a half-time of less than 25 seconds, in strong contrast to Core 2A or pathological amyloids, which in physiological contexts are usually stable and irreversible 4 . We conclude that physiological pH changes regulate rapid Cdc19 amyloid fibril formation and disassembly via reversible protonation of E380 and E392 controlling electrostatic repulsion.…”

Section: Main Textmentioning

confidence: 99%

“…Finally, we speculate that protonation of specific residues within amyloid cores could not only regulate reversible aggregation of pyruvate kinases, but may be a widespread mechanism to control functional amyloid formation and disassembly. Indeed, beyond pyruvate kinases, changes in cytosolic pH have been shown to influence aggregation of other functional amyloids such as peptide hormones 39 , neuropeptides 40 and the memory-associated protein Orb2 4 . For the latter, pH-sensing was proposed to be mediated by histidine residues located in the Orb2 amyloid core 22 .…”

Section: Main Textmentioning

confidence: 99%

“…Interestingly, recent structural studies of functional amyloids highlighted their similarity to pathological aggregates, raising the question of what differentiates functional from toxic aggregates 3 . A key difference between the two resides in the presence of cellular mechanisms that govern functional amyloid formation and disassembly, restricting these processes temporally and spatially 4 . However, although functional amyloids exist in all kingdoms of life, only a handful was shown to be reversible in a physiological context, and the exact molecular mechanisms dissolving functional amyloids remain largely unknown.…”

Section: Main Textmentioning

confidence: 99%

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A conserved mechanism regulates reversible amyloids via pH-sensing regions

Cereghetti

Kissling

Koch

et al. 2022

Preprint

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Amyloids were long viewed as irreversible, pathological aggregates, often associated with neurodegenerative diseases. However, recent insights challenge this view, providing evidence that reversible amyloids can form upon stress conditions and fulfil crucial cellular functions. Yet, the molecular mechanisms regulating functional amyloids and the differences to their pathological counterparts remain poorly understood. Here we investigate the conserved principles of amyloid reversibility by studying the essential metabolic enzyme pyruvate kinase (PK) in yeast and human cells. We demonstrate that PK forms stress-dependent reversible amyloids through a pH-sensitive amyloid core. Stress-induced cytosolic acidification promotes aggregate formation via protonation of specific glutamate (in yeast) or histidine (in human) residues within the amyloid core. Our work thus unravels a conserved and potentially widespread mechanism underlying amyloid functionality and reversibility, fine-tuned to the respective physiological cellular pH range.

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Section: Main Textmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

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A conserved mechanism regulates reversible amyloids via pH-sensing regions

Cereghetti

Kissling

Koch

et al. 2022

Preprint

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“…The genes SALL1, SALL4 and ARID4B contribute from 37% to 53% of the variation in longevity seen across species (table 1b) and are important developmental regulators (Hirsch et al 2015;Buttgereit et al 2016;Wu et al 2019;Bon-Baret et al 2021;GÜven and Terzİ ÇİzmecİoĞlu 2021). Among the other genes, WIPI1 is important for autophagy (Grimmel et al 2015), HIVEP3 for immunity and inflammation processes (Hicar et al 2001;Krovi et al 2020), and FXR1 for the regulation of memory and emotions (Kalueff 2007;Sopova et al 2019;Brown and Török 2021), important traits that have shaped primate evolution.…”

Section: The Rate Of Evolution (Dn/ds) In 67 Genes Positively Correlates With the Evolution Of Longevity And Body Mass Across Primatesmentioning

confidence: 99%

Positive selection and enhancer evolution shaped lifespan and body mass in great apes

Tejada‐Martinez

Avelar

Magalhães

et al. 2021

Preprint

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Within primates, the great apes are outliers both in terms of body size and lifespan, since they include the largest and longest-lived species in the order. Yet, the molecular bases underlying such features are poorly understood. Here, we leveraged an integrated approach to investigate multiple sources of molecular variation across primates, focusing on ~1,550 genes previously described as tumor suppressors, oncogenes, ageing genes in addition to a novel Build of the CellAge database of cell-senescence genes (version 2), herein presented for the first time. Specifically, we analyzed dN/dS rates, positive selection, gene expression (RNA-seq) and gene regulation (ChIP-seq). By analyzing the correlation between dN/dS, maximum lifespan and body mass we identified 67 genes that in primates co-evolved with those traits. Further, we identified 6 genes, important for immunity, neurodevelopment and telomere maintenance (including TERF2), under positive selection in the great ape ancestor. RNA-seq data, generated from the liver of six species representing all the primate lineages, revealed that ~8% of the longevity genes are differentially expressed in apes relative to other primates. Importantly, by integrating RNA-seq with ChIP-seq for H3K27ac (which marks active enhancers), we show that the differentially expressed longevity genes are significantly more likely than expected to be located near a novel “ape-specific” enhancer. Moreover, these particular ape-specific enhancers are enriched for young transposable elements, and specifically SINE-Vntr-Alus (SVAs). In summary, we demonstrate that multiple evolutionary forces have contributed to the evolution of lifespan and body size in primates.

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“…While pathological amyloids are being associated with a growing number of diseases; non-pathological forms also appear in many organisms performing a wide range of normal physiological functions ranging from hormone storage to structural support and defense mechanisms 6,8 . In addition, self-assembly of peptides gains a growing interest in synthetic chemistry, bioengineering and material science as these aggregates can serve as a simple, low cost, green, and tuneable catalysts of chemical reactions or scaffolds and building blocks for nano/ biomaterials.…”

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confidence: 99%

Amyloids in synthetic applications

Török

2022

Sci Rep

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More than a century after the first description of amyloids by Alois Alzheimer, and despite the enormous research efforts since then, the field is still full of surprises. While searching for answers to questions for example on the driving force, mechanism, and regulation of amyloidogenesis, or on the structure, physiological and pathological roles of different amyloid aggregates, unexpected properties are regularly revealed, broadening their application possibilities. This Collection aims to focus on the beneficial sides of amyloid formation, primarily exploring the potential use of amyloids in material science, bioengineering, and synthetic chemistry.

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Functional amyloids in the human body

Cited by 9 publications

References 82 publications

A conserved mechanism regulates reversible amyloids via pH-sensing regions

A conserved mechanism regulates reversible amyloids via pH-sensing regions

Positive selection and enhancer evolution shaped lifespan and body mass in great apes

Amyloids in synthetic applications

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