The formation, function and regulation of amyloids: insights from structural biology

Abstract

Amyloid diseases are characterized by the accumulation of insoluble, β-strand-rich aggregates. The underlying structural conversions are closely associated with cellular toxicity, but can also drive the formation of functional protein assemblies. In recent years, studies in the field of structural studies have revealed astonishing insights into the origins, mechanisms and implications of amyloid formation. Notably, high-resolution crystal structures of peptides in amyloid-like fibrils and prefibrillar oligomers have become available despite their challenging chemical nature. Nuclear magnetic resonance spectroscopy has revealed that dynamic local polymorphisms in the benign form of the prion protein affect the transformation into amyloid fibrils and the transmissibility of prion diseases. Studies of the structures and interactions of chaperone proteins help us to understand how the cellular proteostasis network is able to recognize different stages of aberrant protein folding and prevent aggregation. In this review, we will focus on recent developments that connect the different aspects of amyloid biology and discuss how understanding the process of amyloid formation and the associated defence mechanisms can reveal targets for pharmacological intervention that may become the first steps towards clinically viable treatment strategies.

A spidroin‐derived solubility tag enables controlled aggregation of a designed amyloid protein

“…Amyloid fibrils are built from proteins that form b-strands running perpendicularly to the fibril axis [1][2][3][4][5]. Although some amyloid fibrils are functional [6][7][8][9], they are also associated with several severe diseases, including neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) [1,4,10].…”

Amyloid‐like aggregation of designer bolaamphiphilic peptides: Effect of hydrophobic section and hydrophilic heads

“…1 Known as the result of protein misfolding, amyloid fibrils are generally believed to be the major cause leading to the formation of pathogenic amyloid plaque. 2,3 On the other hand, it has been found that a variety of nonpathogenic proteins could also form amyloid fibrils with normal biological functions, indicating that formation of amyloid fibrils is a prevailing phenomenon in nature. [4][5][6] Amyloidogenic proteins or polypeptides usually came from different tissues and showed very little similarity considering their full amino acid sequences, but the amyloid fibrils they formed shared several characteristic features such as similar morphology, apple-green birefringence after Congo red (CR) staining, and specific fluorescence when binding with thioflavin-T (ThT), suggesting that there might be a common mechanism for the formation of amyloid fibrils by these different proteins or polypeptides.…”

New Insight in The Molecular Mechanisms of Neurodegenerative Disease

“…Following their synthesis on ribosomes as linear chains of amino acids, proteins generally must fold to unique three-dimensional structures to become functionally active. (196) Proteins are essential to cellular metabolism and communication, and they form the framework on which cells and tissues are built. To undertake these roles, most proteins fold into a specific, three-dimensional architecture that is largely determined by their distinctive sequences of amino acids.…”

“…The capacity of the chaperone system to prevent or reverse toxic aggregates declines during aging, facilitating the manifestation of a range of NDDs and other pathologies (Figures 6). (196) Amyloid diseases, or the amyloidoses, are characterized by the deposition of cross-b-sheet amyloid fibrils consisting of misfolded and/or misassembled proteins. (203)(204)(205) The amyloid fibrils that are the pathological hallmark of these disorders can be either deposited systemically or localized to specific organs.…”