Peptides and proteins have been found to possess an inherent tendency to convert from their native functional states into intractable amyloid aggregates. This phenomenon is associated with a range of ...increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidoses. In this review, we describe this field of science with particular reference to the advances that have been made over the last decade in our understanding of its fundamental nature and consequences. We list the proteins that are known to be deposited as amyloid or other types of aggregates in human tissues and the disorders with which they are associated, as well as the proteins that exploit the amyloid motif to play specific functional roles in humans. In addition, we summarize the genetic factors that have provided insight into the mechanisms of disease onset. We describe recent advances in our knowledge of the structures of amyloid fibrils and their oligomeric precursors and of the mechanisms by which they are formed and proliferate to generate cellular dysfunction. We show evidence that a complex proteostasis network actively combats protein aggregation and that such an efficient system can fail in some circumstances and give rise to disease. Finally, we anticipate the development of novel therapeutic strategies with which to prevent or treat these highly debilitating and currently incurable conditions.
Peptides or proteins convert under some conditions from their soluble forms into highly ordered fibrillar aggregates. Such transitions can give rise to pathological conditions ranging from ...neurodegenerative disorders to systemic amyloidoses. In this review, we identify the diseases known to be associated with formation of fibrillar aggregates and the specific peptides and proteins involved in each case. We describe, in addition, that living organisms can take advantage of the inherent ability of proteins to form such structures to generate novel and diverse biological functions. We review recent advances toward the elucidation of the structures of amyloid fibrils and the mechanisms of their formation at a molecular level. Finally, we discuss the relative importance of the common main-chain and side-chain interactions in determining the propensities of proteins to aggregate and describe some of the evidence that the oligomeric fibril precursors are the primary origins of pathological behavior.
Lyme disease is the most common tick-borne disease in temperate regions of North America, Europe and Asia, and the number of reported cases has increased in many regions as landscapes have been ...altered. Although there has been extensive work on the ecology and epidemiology of this disease in both Europe and North America, substantial uncertainty exists about fundamental aspects that determine spatial and temporal variation in both disease risk and human incidence, which hamper effective and efficient prevention and control. Here we describe areas of consensus that can be built on, identify areas of uncertainty and outline research needed to fill these gaps to facilitate predictive models of disease risk and the development of novel disease control strategies. Key areas of uncertainty include: (i) the precise influence of deer abundance on tick abundance, (ii) how tick populations are regulated, (iii) assembly of host communities and tick-feeding patterns across different habitats, (iv) reservoir competence of host species, and (v) pathogenicity for humans of different genotypes of Borrelia burgdorferi. Filling these knowledge gaps will improve Lyme disease prevention and control and provide general insights into the drivers and dynamics of this emblematic multi-host–vector-borne zoonotic disease.
This article is part of the themed issue ‘Conservation, biodiversity and infectious disease: scientific evidence and policy implications'.
The conversion of proteins from their soluble states into well-organized fibrillar aggregates is associated with a wide range of pathological conditions, including neurodegenerative diseases and ...systemic amyloidoses. In this review, we discuss the mechanism of aggregation of globular proteins under conditions in which they are initially folded. Although a conformational change of the native state is generally necessary to initiate aggregation, we show that a transition across the major energy barrier for unfolding is not essential and that aggregation may well be initiated from locally unfolded states that become accessible, for example, via thermal fluctuations occurring under physiological conditions. We review recent evidence on this topic and discuss its significance for understanding the onset and potential inhibition of protein aggregation in the context of diseases.
Protein folding and misfolding Dobson, Christopher M
Nature (London),
12/2003, Letnik:
426, Številka:
6968
Journal Article
Recenzirano
The manner in which a newly synthesized chain of amino acids transforms itself into a perfectly folded protein depends both on the intrinsic properties of the amino-acid sequence and on multiple ...contributing influences from the crowded cellular milieu. Folding and unfolding are crucial ways of regulating biological activity and targeting proteins to different cellular locations. Aggregation of misfolded proteins that escape the cellular quality-control mechanisms is a common feature of a wide range of highly debilitating and increasingly prevalent diseases.
The twin concepts of zooprophylaxis and the dilution effect originated with vector-borne diseases (malaria), were driven forward by studies on Lyme borreliosis and have now developed into the mantra ...“biodiversity protects against disease”. The basic idea is that by diluting the assemblage of transmission-competent hosts with non-competent hosts, the probability of vectors feeding on transmission-competent hosts is reduced and so the abundance of infected vectors is lowered. The same principle has recently been applied to other infectious disease systems – tick-borne, insect-borne, indirectly transmitted via intermediate hosts, directly transmitted. It is claimed that the presence of extra species of various sorts, acting through a variety of distinct mechanisms, causes the prevalence of infectious agents to decrease. Examination of the theoretical and empirical evidence for this hypothesis reveals that it applies only in certain circumstances even amongst tick-borne diseases, and even less often if considering the correct metric – abundance rather than prevalence of infected vectors. Whether dilution or amplification occurs depends more on specific community composition than on biodiversity per se. We warn against raising a straw man, an untenable argument easily dismantled and dismissed. The intrinsic value of protecting biodiversity and ecosystem function outweighs this questionable utilitarian justification.
Many neurodegenerative disorders, including Alzheimer's, Parkinson's and the prion diseases, are characterized by a conformational conversion of normally soluble proteins or peptides into ...pathological species, by a process of misfolding and self-assembly that leads ultimately to the formation of amyloid fibrils. Recent studies support the idea that multiple intermediate species with a wide variety of degrees of neuronal toxicity are generated during such processes. The development of a high level of knowledge of the nature and structure of the pathogenic amyloid species would significantly enhance efforts to underline the molecular origins of these disorders and also to develop both accurate diagnoses and effective therapeutic interventions for these types of conditions. In this review, we discuss recent biophysical and structural information concerning different types of amyloid aggregates and the way in which such information can guide rational therapeutic approaches designed to target specific pathogenic events that occur during the development of these highly debilitating and increasingly common diseases.
Nature and Regulation of Protein Folding on the Ribosome Waudby, Christopher A.; Dobson, Christopher M.; Christodoulou, John
Trends in biochemical sciences (Amsterdam. Regular ed.),
November 2019, 2019-11-00, 20191101, Letnik:
44, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Co-translational protein folding is an essential process by which cells ensure the safe and efficient production and assembly of new proteins in their functional native states following biosynthesis ...on the ribosome. In this review, we describe recent progress in probing the changes during protein synthesis of the free energy landscapes that underlie co-translational folding and discuss the critical coupling between these landscapes and the rate of translation that ultimately determines the success or otherwise of the folding process. Recent developments have revealed a variety of mechanisms by which both folding and translation can be modulated or regulated, and we discuss how these effects are utilised by the cell to optimise the outcome of protein biosynthesis.
Many proteins can begin to fold and begin to assemble their quaternary structure during biosynthesis on the ribosome.Co-translational folding is a nonequilibrium process, the outcome of which is dependent on the interplay between the rate of protein folding and the rate of translation by the ribosome.Co-translational folding takes place across a series of free energy landscapes, encoded in the amino acid sequence, that depend on the length of the nascent chain and can be modulated by interactions with the ribosome surface and with molecular chaperones.The kinetics of protein synthesis can vary in a sequence-specific manner encoded in the genome.Through a combination of these effects, co-translational folding pathways may be tuned to maximise the efficiency of protein biosynthesis.
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.
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