The aggregation of proteins into structures known as amyloids is observed in many neurodegenerative diseases, including Alzheimer's disease. Amyloids are composed of pairs of tightly interacting, ...many stranded and repetitive intermolecular β-sheets, which form the cross-β-sheet structure. This structure enables amyloids to grow by recruitment of the same protein and its repetition can transform a weak biological activity into a potent one through cooperativity and avidity. Amyloids therefore have the potential to self-replicate and can adapt to the environment, yielding cell-to-cell transmissibility, prion infectivity and toxicity.
Amyloids are highly ordered cross-β sheet protein aggregates associated with many diseases including Alzheimer's disease, but also with biological functions such as hormone storage. The cross-β sheet ...entity comprising an indefinitely repeating intermolecular β sheet motif is unique among protein folds. It grows by recruitment of the corresponding amyloid protein, while its repetitiveness can translate what would be a nonspecific activity as monomer into a potent one through cooperativity. Furthermore, the one-dimensional crystal-like repeat in the amyloid provides a structural framework for polymorphisms. This review summarizes the recent high-resolution structural studies of amyloid fibrils in light of their biological activities. We discuss how the unique properties of amyloids gives rise to many activities and further speculate about currently undocumented biological roles for the amyloid entity. In particular, we propose that amyloids could have existed in a prebiotic world, and may have been the first functional protein fold in living cells.
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The second law of thermodynamics, with its positive change of entropy for a system not in equilibrium, defines an arrow of time. Interestingly, also, causality, which is the connection between a ...cause and an effect, requests a direction of time by definition. It is noted that no other standard physical theories show this property. It is the attempt of this work to connect causality with entropy, which is possible by defining time as the metric of causality. Under this consideration that time appears only through a cause–effect relationship (“measured”, typically, in an apparatus called clock), it is demonstrated that time must be discrete in nature and cannot be continuous as assumed in all standard theories of physics including general and special relativity, and classical physics. The following lines of reasoning include: (i) (mechanical) causality requests that the cause must precede its effect (i.e., antecedence) requesting a discrete time interval >0. (ii) An infinitely small time step d t > 0 is thereby not sufficient to distinguish between cause and effect as a mathematical relationship between the two (i.e., Poisson bracket) will commute at a time interval d t , while not evidently within discrete time steps Δ t . As a consequence of a discrete time, entropy emerges (Riek, 2014) connecting causality and entropy to each other.
Nuclear Magnetic Resonance (NMR) spectroscopy is a major technique in structural biology with over 11,800 protein structures deposited in the Protein Data Bank. NMR can elucidate structures and ...dynamics of small and medium size proteins in solution, living cells, and solids, but has been limited by the tedious data analysis process. It typically requires weeks or months of manual work of a trained expert to turn NMR measurements into a protein structure. Automation of this process is an open problem, formulated in the field over 30 years ago. We present a solution to this challenge that enables the completely automated analysis of protein NMR data within hours after completing the measurements. Using only NMR spectra and the protein sequence as input, our machine learning-based method, ARTINA, delivers signal positions, resonance assignments, and structures strictly without human intervention. Tested on a 100-protein benchmark comprising 1329 multidimensional NMR spectra, ARTINA demonstrated its ability to solve structures with 1.44 Å median RMSD to the PDB reference and to identify 91.36% correct NMR resonance assignments. ARTINA can be used by non-experts, reducing the effort for a protein assignment or structure determination by NMR essentially to the preparation of the sample and the spectra measurements.
The hidden world of amyloid biology has suddenly snapped into atomic-level focus, revealing over 80 amyloid protein fibrils, both pathogenic and functional. Unlike globular proteins, amyloid proteins ...flatten and stack into unbranched fibrils. Stranger still, a single protein sequence can adopt wildly different two-dimensional conformations, yielding distinct fibril polymorphs. Thus, an amyloid protein may define distinct diseases depending on its conformation. At the heart of this conformational variability lies structural frustrations. In functional amyloids, evolution tunes frustration levels to achieve either stability or sensitivity according to the fibril’s biological function, accounting for the vast versatility of the amyloid fibril scaffold.
A wealth of recent amyloid structures begins to illuminate these puzzling protein conformations, shedding light on how and why different conformations contribute to cellular function or disease.
In diseases called tauopathies, misfolded tau proteins form aggregates called fibrils. Fibrils from nine different tauopathies show that tau misfolds in many ways, enabling the diseases to be ...classified according to fibril structure.
The diversity of protein folds is derived from the diversity of the underlying proteome. Such diversity must have originated from a so-called common ancestor: a hypothetical fold whose identity will, ...in all likelihood, never be known. Nonetheless, hypotheses exist to explain the evolution of protein folds. When formulating such hypotheses as done here, the entire repertoire of polypeptide structure, from well-defined tertiary structures and molten globule states to intrinsically disordered proteins and oligomeric aggregates, is worth considering. It is the aim of this short essay to discuss the hypothesis that one type of protein aggregate—the cross-β-sheet motif—was the first functional protein fold, that is, the common ancestor fold. Support for this hypothesis comes from the observations that (i) short peptides with simple amino acid sequences are able to form the cross-β-sheet structure, (ii) amyloids can be very stable under harsh conditions, (iii) amyloids can self-assemble in complex mixtures, (iv) amyloids have many potent activities that are attributable to the inherent repetitiveness of the structure, and (v) the proteomes of modern organisms appear to have evolved away from the more amyloidogenic sequences of older organisms, suggesting that amyloids were more ubiquitous earlier in the evolution of modern protein folds.
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► The amyloid fold is unique in the protein fold universe. ► The amyloid fold has many potential activities. ► It is suggested that the amyloid fold may have been the first common ancestor fold.
We present NMRtist, an online platform that combines deep learning, large-scale optimization and cloud computing to automate protein NMR spectra analysis. Our website provides virtual storage for NMR ...spectra deposition together with a set of applications designed for automated peak picking, chemical shift assignment and protein structure determination. The system can be used by non-experts and allows protein assignments and structures to be determined within hours after the measurements, strictly without any human intervention.
NMRtist is freely available to non-commercial users at https://nmrtist.org.
Supplementary data are available at Bioinformatics online.
Amyloid diseases are global epidemics with profound health, social and economic implications and yet remain without a cure. This dire situation calls for research into the origin and pathological ...manifestations of amyloidosis to stimulate continued development of new therapeutics. In basic science and engineering, the cross-β architecture has been a constant thread underlying the structural characteristics of pathological and functional amyloids, and realizing that amyloid structures can be both pathological and functional in nature has fuelled innovations in artificial amyloids, whose use today ranges from water purification to 3D printing. At the conclusion of a half century since Eanes and Glenner's seminal study of amyloids in humans, this review commemorates the occasion by documenting the major milestones in amyloid research to date, from the perspectives of structural biology, biophysics, medicine, microbiology, engineering and nanotechnology. We also discuss new challenges and opportunities to drive this interdisciplinary field moving forward.
The amylome is the universe of proteins that are capable of forming amyloid-like fibrils. Here we investigate the factors that enable a protein to belong to the amylome. A major factor is the ...presence in the protein of a segment that can form a tightly complementary interface with an identical segment, which permits the formation of a steric zipper--two self-complementary beta sheets that form the spine of an amyloid fibril. Another factor is sufficient conformational freedom of the self-complementary segment to interact with other molecules. Using RNase A as a model system, we validate our fibrillogenic predictions by the 3D profile method based on the crystal structure of NNQQNY and demonstrate that a specific residue order is required for fiber formation. Our genome-wide analysis revealed that self-complementary segments are found in almost all proteins, yet not all proteins form amyloids. The implication is that chaperoning effects have evolved to constrain self-complementary segments from interaction with each other.
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