Amyloid-type Protein Aggregation and Prion-like Properties of Amyloids

Willbold, Dieter; Strodel, Birgit; Schröder, Gunnar F.; Hoyer, Wolfgang; Heise, Henrike

doi:10.1021/acs.chemrev.1c00196

Cited by 133 publications

(131 citation statements)

References 278 publications

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“…Recently, with the advance in state-of-the-art structural biology techniques and equipment, several new fibril structure details have been reported at atomic and near-atomic level (for review see ref. [ 71 ]). It is quite bewildering to note the differences in handedness, fibrillar length, helical axis position, and pitch length.…”

Section: Discussionmentioning

confidence: 99%

Conformational heterogeneity coupled with β-fibril formation of a scaffold protein involved in chronic mental illnesses

et al. 2021

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Chronic mental illnesses (CMIs) pose a significant challenge to global health due to their complex and poorly understood etiologies and hence, absence of causal therapies. Research of the past two decades has revealed dysfunction of the disrupted in schizophrenia 1 (DISC1) protein as a predisposing factor involved in several psychiatric disorders. DISC1 is a multifaceted protein that serves myriads of functions in mammalian cells, for instance, influencing neuronal development and synapse maintenance. It serves as a scaffold hub forming complexes with a variety (~300) of partners that constitute its interactome. Herein, using combinations of structural and biophysical tools, we demonstrate that the C-region of the DISC1 protein is highly polymorphic, with important consequences for its physiological role. Results from solid-state NMR spectroscopy and electron microscopy indicate that the protein not only forms symmetric oligomers but also gives rise to fibrils closely resembling those found in certain established amyloid proteinopathies. Furthermore, its aggregation as studied by isothermal titration calorimetry (ITC) is an exergonic process, involving a negative enthalpy change that drives the formation of oligomeric (presumably tetrameric) species as well as β-fibrils. We have been able to narrow down the β-core region participating in fibrillization to residues 716–761 of full-length human DISC1. This region is absent in the DISC1Δ22aa splice variant, resulting in reduced association with proteins from the dynein motor complex, viz., NDE-like 1 (NDEL1) and lissencephaly 1 (LIS1), which are crucial during mitosis. By employing surface plasmon resonance, we show that the oligomeric DISC1 C-region has an increased affinity and shows cooperativity in binding to LIS1 and NDEL1, in contrast to the noncooperative binding mode exhibited by the monomeric version. Based on the derived structural models, we propose that the association between the binding partners involves two neighboring subunits of DISC1 C-region oligomers. Altogether, our findings highlight the significance of the DISC1 C-region as a crucial factor governing the balance between its physiological role as a multifunctional scaffold protein and aggregation-related aberrations with potential significance for disease.

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Section: Discussionmentioning

confidence: 99%

Conformational heterogeneity coupled with β-fibril formation of a scaffold protein involved in chronic mental illnesses

et al. 2021

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“…In these cases, peptide oligomers organize in β-sheet structures, which lead to the sequential formation of protofilaments, then fibrils, and finally amyloid plaques [ 42 , 43 , 44 ]. The investigation of the mechanisms leading to amyloid fibrillization has helped in the identification of the short KLVFF motif of the Aβ40 and Aβ42 fragments as the factors responsible for the first steps of peptide aggregation [ 45 , 46 ]. With a reductionist approach, Gazit and co-workers used the FF dipeptide to engineer a variety of nanostructures (tapes, nanotubes, fibrils, etc.)…”

Section: The Bottom-up Approach To Hierarchical Self-assemblymentioning

confidence: 99%

Peptide Self-Assembled Nanostructures: From Models to Therapeutic Peptides

2022

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Self-assembly is the most suitable approach to obtaining peptide-based materials on the nano- and mesoscopic scales. Applications span from peptide drugs for personalized therapy to light harvesting and electron conductive media for solar energy production and bioelectronics, respectively. In this study, we will discuss the self-assembly of selected model and bioactive peptides, in particular reviewing our recent work on the formation of peptide architectures of nano- and mesoscopic size in solution and on solid substrates. The hierarchical and cooperative characters of peptide self-assembly will be highlighted, focusing on the structural and dynamical properties of the peptide building blocks and on the nature of the intermolecular interactions driving the aggregation phenomena in a given environment. These results will pave the way for the understanding of the still-debated mechanism of action of an antimicrobial peptide (trichogin GA IV) and the pharmacokinetic properties of a peptide drug (semaglutide) currently in use for the therapy of type-II diabetes.

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“…These fibrous deposits have been linked to systemic and neuro-debilitating diseases, such as atherosclerosis, Alzheimer's, Parkinson's, and others. 171,172 Curiously, on the other hand, experimental studies have suggested that EMFs may be used as a therapeutic tool for the breakdown of fibrils implicated in Alzheimer's disease. 15,57 Therefore, an improved understanding of the effects of radiofrequency radiation on biomolecules and their implications in disease processes at the molecular level has been the goal of several research groups.…”

Section: Recent Case Studiesmentioning

confidence: 99%