The Enigma of Amyloid Forming Proteins: Insights From Molecular Simulations

Molecular level insight into the interplay between protein sequence, structure, and conformational dynamics is crucial for the comprehensive understanding of protein folding, misfolding, and aggregation phenomena that are pertinent to the formation of amyloid fibrils implicated in several degenerative diseases. Computational modelling provides insight into protein behaviour at spatial and temporal resolution still largely outside the reach of experiments. Herein we present an account of our theoretical modelling research conducted in collaboration with several experimental groups where we explored the effects of local environment on the structure and aggregation propensity of several types of amyloidogenic peptides and proteins, including apolipoprotein C-II, insulin, amylin, and amyloid-β using a variety of computational approaches.

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Effect of Oxidation and Mutation on the Conformational Dynamics and Fibril Assembly of Amyloidogenic Peptides Derived from Apolipoprotein C-II

The Journal of Physical Chemistry B ◽

10.1021/jp903842u ◽

2009 ◽

Vol 113 (42) ◽

pp. 14006-14014 ◽

Cited By ~ 13

Author(s):

F. S. Legge ◽

K. J. Binger ◽

M. D. W. Griffin ◽

G. J. Howlett ◽

D. Scanlon ◽

...

Keyword(s):

Conformational Dynamics ◽

Apolipoprotein C ◽

Amyloidogenic Peptides

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Extract from the Marine Seaweed Padina pavonica Protects Mitochondrial Biomembranes from Damage by Amyloidogenic Peptides

Molecules ◽

10.3390/molecules26051444 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1444

Author(s):

Mario Caruana ◽

Angelique Camilleri ◽

Maria Ylenia Farrugia ◽

Stephanie Ghio ◽

Michaela Jakubíčková ◽

...

Keyword(s):

Lipid Membranes ◽

Amyloid Fibrils ◽

Biological Activities ◽

Amyloid Β ◽

Brown Seaweed ◽

Inhibitory Effect ◽

Therapeutic Value ◽

Amyloid Oligomers ◽

Amyloidogenic Peptides ◽

Aggregate Structures

The identification of compounds which protect the double-membrane of mitochondrial organelles from disruption by toxic confomers of amyloid proteins may offer a therapeutic strategy to combat human neurodegenerative diseases. Here, we exploited an extract from the marine brown seaweed Padina pavonica (PPE) as a vital source of natural bioactive compounds to protect mitochondrial membranes against insult by oligomeric aggregates of the amyloidogenic proteins amyloid-β (Aβ), α-synuclein (α-syn) and tau, which are currently considered to be major targets for drug discovery in Alzheimer’s disease (AD) and Parkinson’s disease (PD). We show that PPE manifested a significant inhibitory effect against swelling of isolated mitochondria exposed to the amyloid oligomers, and attenuated the release of cytochrome c from the mitochondria. Using cardiolipin-enriched synthetic lipid membranes, we also show that dye leakage from fluorophore-loaded vesicles and formation of channel-like pores in planar bilayer membranes are largely prevented by incubating the oligomeric aggregates with PPE. Lastly, we demonstrate that PPE curtails the ability of Aβ42 and α-syn monomers to self-assemble into larger β-aggregate structures, as well as potently disrupts their respective amyloid fibrils. In conclusion, the mito-protective and anti-aggregator biological activities of Padina pavonica extract may be of therapeutic value in neurodegenerative proteinopathies, such as AD and PD.

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Functionalization of amyloid fibrils via the Bri2 BRICHOS domain

Scientific Reports ◽

10.1038/s41598-020-78732-1 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Henrik Biverstål ◽

Rakesh Kumar ◽

Anna Katharina Schellhaus ◽

Médoune Sarr ◽

Nico P. Dantuma ◽

...

Keyword(s):

Amyloid Fibrils ◽

Cultured Cells ◽

Cell Attachment ◽

Amyloid Β ◽

Attachment Sites ◽

Human Proteins ◽

Scaffold Materials ◽

Amyloidogenic Peptides ◽

Aβ Fibrils

AbstractAmyloid fibrils are mechanically robust and partly resistant to proteolytic degradation, making them potential candidates for scaffold materials in cell culture, tissue engineering, drug delivery and other applications. Such applications of amyloids would benefit from the possibility to functionalize the fibrils, for example by adding growth factors or cell attachment sites. The BRICHOS domain is found in a family of human proteins that harbor particularly amyloid-prone regions and can reduce aggregation as well as toxicity of several different amyloidogenic peptides. Recombinant human (rh) BRICHOS domains have been shown to bind to the surface of amyloid-β (Aβ) fibrils by immune electron microscopy. Here we produce fusion proteins between mCherry and rh Bri2 BRICHOS and show that they can bind to different amyloid fibrils with retained fluorescence of mCherry in vitro as well as in cultured cells. This suggests a “generic” ability of the BRICHOS domain to bind fibrillar surfaces that can be used to synthesize amyloid decorated with different protein functionalities.

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The physical chemistry of the amyloid phenomenon: thermodynamics and kinetics of filamentous protein aggregation

Essays in Biochemistry ◽

10.1042/bse0560011 ◽

2014 ◽

Vol 56 ◽

pp. 11-39 ◽

Cited By ~ 31

Author(s):

Alexander K. Buell ◽

Christopher M. Dobson ◽

Tuomas P.J. Knowles

Keyword(s):

Protein Aggregation ◽

Molecular Chaperones ◽

Amyloid Fibrils ◽

Theoretical Modelling ◽

Amyloid Formation ◽

Recent Developments ◽

The Individual ◽

Kinetics Of ◽

Soluble State ◽

Insight Into

In this chapter, we present an overview of the kinetics and thermodynamics of protein aggregation into amyloid fibrils. The perspective we adopt is largely experimental, but we also discuss recent developments in data analysis and we show that only a combination of well-designed experiments with appropriate theoretical modelling is able to provide detailed mechanistic insight into the complex pathways of amyloid formation. In the first part of the chapter, we describe measurements of the thermodynamic stability of the amyloid state with respect to the soluble state of proteins, as well as the magnitude and origin of this stability. In the second part, we discuss in detail the kinetics of the individual molecular steps in the overall mechanism of the conversion of soluble protein into amyloid fibrils. Finally, we highlight the effects of external factors, such as salt type and concentration, chemical denaturants and molecular chaperones on the kinetics of aggregation.

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Becoming the World's Biggest Brewer

10.1093/oso/9780198829089.001.0001 ◽

2019 ◽

Author(s):

Kenneth Bertrams ◽

Julien Del Marmol ◽

Sander Geerts ◽

Eline Poelmans

Keyword(s):

Local Environment ◽

Success Story ◽

Beer Industry ◽

National Market ◽

The World ◽

History Of ◽

Nineteenth And Twentieth Centuries ◽

The 1960S ◽

Global Company ◽

Insight Into

AB InBev is today’s uncontested world leader of the beer market. It represents over 20 per cent of global beer sales, with more than 450 million hectolitres a year flowing all around the world. Its Belgian predecessor, Interbrew, was a success story stemming from the 1971 secret merger of the country’s two leading brewers: Artois and Piedboeuf. Based on first-hand material originating from company and private archives as well as interviews with managers and key family actors, this is the first study to explore the history of the company through the nineteenth and twentieth centuries.The story starts in the mid-nineteenth century with the scientific breakthroughs that revolutionized the beer industry and allowed both Artois and Piedboeuf to prosper in a local environment. Instrumental in this respect were the respective families and their successive heirs in stabilizing and developing their firms. Despite the intense difficulties of two world wars in the decades to follow, they emerged stronger than ever and through the 1960s became undisputed leaders in the national market. Then, in an unprecedented move, Artois and Piedboeuf secretly merged their shareholding in 1971, though keeping their operations separate until 1987 when they openly and operationally merged to become Interbrew. Throughout their histories Artois, Piedboeuf, and their successor companies have kept a controlling family ownership. This book provides a unique insight into both the complex history of these three family breweries and their path to becoming a prominent global company, and the growth and consolidation of the beer market through the nineteenth and twentieth centuries.

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Molecular Insight into Cu2+-Induced Conformational Transitions of Amyloid β-Protein from Fast Kinetic Analysis and Molecular Dynamics Simulations

ACS Chemical Neuroscience ◽

10.1021/acschemneuro.0c00502 ◽

2021 ◽

Author(s):

Shaoying Xu ◽

Wenjuan Wang ◽

Xiaoyan Dong ◽

Yan Sun

Keyword(s):

Molecular Dynamics ◽

Kinetic Analysis ◽

Molecular Dynamics Simulations ◽

Amyloid Β ◽

Conformational Transitions ◽

Amyloid Β Protein ◽

Β Protein ◽

Fast Kinetic ◽

Dynamics Simulations ◽

Insight Into

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CLAC binds to amyloid β peptides through the positively charged amino acid cluster within the collagenous domain 1 and inhibits formation of amyloid fibrils. Vol. 280 (2005) 8596–8605

Journal of Biological Chemistry ◽

10.1016/s0021-9258(20)66082-3 ◽

2005 ◽

Vol 280 (15) ◽

pp. 15484

Author(s):

Yoshihide Osada ◽

Tadafumi Hashimoto ◽

Akiko Nishimura ◽

Yuko Matsuo ◽

Tomoko Wakabayashi ◽

...

Keyword(s):

Amino Acid ◽

Amyloid Fibrils ◽

Amyloid Β ◽

Collagenous Domain ◽

Amino Acid Cluster ◽

Positively Charged

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Cryo-EM structure of amyloid fibrils formed by the entire low complexity domain of TDP-43

Nature Communications ◽

10.1038/s41467-021-21912-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Qiuye Li ◽

W. Michael Babinchak ◽

Witold K. Surewicz

Keyword(s):

Amyloid Fibrils ◽

Low Complexity ◽

Structural Features ◽

Protein Fragments ◽

Hydrophobic Residues ◽

Backbone Conformation ◽

Hydrophobic Amino Acids ◽

Insight Into ◽

Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis and several other neurodegenerative diseases are associated with brain deposits of amyloid-like aggregates formed by the C-terminal fragments of TDP-43 that contain the low complexity domain of the protein. Here, we report the cryo-EM structure of amyloid formed from the entire TDP-43 low complexity domain in vitro at pH 4. This structure reveals single protofilament fibrils containing a large (139-residue), tightly packed core. While the C-terminal part of this core region is largely planar and characterized by a small proportion of hydrophobic amino acids, the N-terminal region contains numerous hydrophobic residues and has a non-planar backbone conformation, resulting in rugged surfaces of fibril ends. The structural features found in these fibrils differ from those previously found for fibrils generated from short protein fragments. The present atomic model for TDP-43 LCD fibrils provides insight into potential structural perturbations caused by phosphorylation and disease-related mutations.

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