The amyloid state of proteins: A boon or bane?

Hassan, Md Nadir; Nabi, Faisal; Khan, Asra Nasir; Hussain, Murtaza; Siddiqui, Waseem Ahmad; Uversky, Vladimir N.; Khan, Rizwan Hasan

doi:10.1016/j.ijbiomac.2022.01.115

Cited by 16 publications

(9 citation statements)

References 295 publications

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“…Furthermore, insulin dysfunction has been linked directly or indirectly to increased risks of developing neurodegenerative syndromes [ 17 ]. Nevertheless, there is increasing evidence that amyloids may also play a physiological role, although this is far from being understood for human amyloids, while a clearer scenario has emerged for other organisms, such as bacteria [ 18 ]. Despite the many roles that insulin fibrillation may play, pertaining to various facets of human health, it is not as widely studied as other amyloid proteins, although it clearly deserves further investigation.…”

Section: Introductionmentioning

confidence: 99%

Peptide Inhibitors of Insulin Fibrillation: Current and Future Challenges

Rosetti

Marchesan

2023

IJMS

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Amyloidoses include a large variety of local and systemic diseases that share the common feature of protein unfolding or refolding into amyloid fibrils. The most studied amyloids are those directly involved in neurodegenerative diseases, while others, such as those formed by insulin, are surprisingly far less studied. Insulin is a very important polypeptide that plays a variety of biological roles and, first and foremost, is at the basis of the therapy of diabetic patients. It is well-known that it can form fibrils at the site of injection, leading to inflammation and immune response, in addition to other side effects. In this concise review, we analyze the current knowledge on insulin fibrillation, with a focus on the development of peptide-based inhibitors, which are promising candidates for their biocompatibility but still pose challenges to their effective use in therapy.

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Section: Introductionmentioning

confidence: 99%

Peptide Inhibitors of Insulin Fibrillation: Current and Future Challenges

Rosetti

Marchesan

2023

IJMS

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“…Amyloids are proteins that have the ability to transition from monomers into insoluble fibers that share a common quaternary structure enriched in beta-sheets stacked in the so-called cross-beta architecture 3 . These proteins have traditionally been studied in the context of human diseases, as several amyloid proteins and peptides are considered the causative agents of many protein misfolding disorders that lead to known neurodegenerative pathologies 4 , 5 . However, the beneficial role of amyloid proteins in many biological functions required for homeostasis is currently well established, which is why part of this broad family of proteins has been subclassified as functional amyloids 5 .…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of the N-terminal half of TasA during amyloid-like assembly and its contribution to Bacillus subtilis biofilm formation

Cámara-Almirón,

Domínguez-García,

El Mammeri

et al. 2023

npj Biofilms Microbiomes

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Biofilms are bacterial communities that result from a cell differentiation process leading to the secretion of an extracellular matrix (ECM) by part of the population. In Bacillus subtilis, the main protein component of the ECM is TasA, which forms a fiber-based scaffold that confers structure to the ECM. The N-terminal half of TasA is strongly conserved among Bacillus species and contains a protein domain, the rigid core (RcTasA), which is critical for the structural and functional properties of the recombinant protein. In this study, we demonstrate that recombinantly purified RcTasA in vitro retains biochemical properties previously observed for the entire protein. Further analysis of the RcTasA amino acid sequence revealed two aggregation-prone stretches and a region of imperfect amino acid repeats, which are known to contribute to functional amyloid assembly. Biochemical characterization of these stretches found in RcTasA revealed their amyloid-like capacity in vitro, contributing to the amyloid nature of RcTasA. Moreover, the study of the imperfect amino acid repeats revealed the critical role of residues D64, K68 and D69 in the structural function of TasA. Experiments with versions of TasA carrying the substitutions D64A and K68AD69A demonstrated a partial loss of function of the protein either in the assembly of the ECM or in the stability of the core and amyloid-like properties. Taken together, our findings allow us to better understand the polymerization process of TasA during biofilm formation and provide knowledge into the sequence determinants that promote the molecular behavior of protein filaments in bacteria.

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“…These proteins have traditionally been studied in the context of human diseases, as several amyloid proteins and peptides are considered the causative agents of many protein misfolding disorders that lead to known neurodegenerative pathologies 2,3 . However, the beneficial role of amyloid proteins in many biological functions required for homeostasis is currently well established, which is why part of this broad family of proteins has been subclassified as functional amyloids 3 . Alternative functions reported for these proteins in bacteria are antimicrobial, promotion of bacterial virulence in plants or providing a structural scaffold during biofilm formation (see [4][5][6] for extended reviews on the subject).…”

Section: Introductionmentioning

confidence: 99%

“…Amyloids are proteins that have the ability to transition from monomers into insoluble fibers that share a common quaternary structure enriched in beta-sheets stacked in the so-called cross-beta architecture 1 . These proteins have traditionally been studied in the context of human diseases, as several amyloid proteins and peptides are considered the causative agents of many protein misfolding disorders that lead to known neurodegenerative pathologies 2, 3 . However, the beneficial role of amyloid proteins in many biological functions required for homeostasis is currently well established, which is why part of this broad family of proteins has been subclassified as functional amyloids 3 .…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of the N-terminal half of TasA during functional amyloid assembly and its contribution toBacillus subtilisbiofilm formation

Cámara-Almirón

Domínguez-García

Mammeri

et al. 2023

Preprint

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Biofilms are bacterial communities that result from a cell differentiation process that leads to the secretion of an extracellular matrix (ECM) by part of the bacterial population. In Bacillus subtilis, the main protein component of the ECM is the functional amyloid TasA, which forms a fiber-based scaffold that confers structure to the ECM. The N-terminal half of TasA is strongly conserved among Bacillus species and contains a protein domain, the amyloid core (AcTasA), which is critical for the formation of the amyloid architecture. In this study, we demonstrate that recombinantly purified AcTasA in vitro retains biochemical properties previously observed for the entire protein. Further analysis of the AcTasA amino acid sequence revealed two amyloidogenic stretches and a region of imperfect amino acid repeats, which are known to contribute to functional amyloid assembly. Biochemical characterization of these amyloidogenic stretches found in AcTasA revealed their amyloid capacity in vitro, contributing to the amyloid nature of AcTasA. Moreover, the study of the imperfect amino acid repeats revealed the critical role of residues D64, K68 and D69 in the structural function of TasA. In vivo and in vitro experiments with versions of TasA carrying the substitutions D64A, K68A, and D69A demonstrated a partial loss of function of the protein either in the assembly of the ECM or in the stability of the core and amyloid polymerization. Taken together, our findings allow us to better understand the polymerization process of TasA during biofilm formation and provide knowledge into the sequence determinants that promote the molecular behavior of functional amyloids.

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The amyloid state of proteins: A boon or bane?

Cited by 16 publications

References 295 publications

Peptide Inhibitors of Insulin Fibrillation: Current and Future Challenges

Peptide Inhibitors of Insulin Fibrillation: Current and Future Challenges

Molecular characterization of the N-terminal half of TasA during amyloid-like assembly and its contribution to Bacillus subtilis biofilm formation

Molecular characterization of the N-terminal half of TasA during functional amyloid assembly and its contribution toBacillus subtilisbiofilm formation

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