FEBS Letters

doi: 10.1016/S0014-5793(09)00580-8pmid: N/A

Hammarström, Per

doi: 10.1016/j.febslet.2009.07.016pmid: 19616000

Luheshi, Leila M.; Dobson, Christopher M.

doi: 10.1016/j.febslet.2009.06.030pmid: 19545568

Protein misfolding and aggregation are pathognomic for a number of the most common age‐related degenerative diseases. Great progress has been made in studying protein aggregation in the test tube and also in replicating protein aggregation in vertebrate animal models of these diseases. However, we argue here that the development and effective integration of emerging techniques such as the methods of nanoscience and the use of invertebrate models are now providing powerful new opportunities to advance our current understanding of the fundamental origins of these disorders.

White, Duncan A.; Buell, Alexander K.; Dobson, Christopher M.; Welland, Mark E.; Knowles, Tuomas P.J.

doi: 10.1016/j.febslet.2009.06.008pmid: 19523953

Uncontrolled fibrous protein aggregation is implicated in a range of aberrant biological phenomena. Much effort has consequently been directed towards establishing quantitative in vitro assays of this process with the aim of probing amyloid growth in molecular detail as well as elucidating the effect of additional species on this reaction. In this paper, we discuss some recent approaches based on label‐free technologies focussed on achieving these objectives. Several biosensor techniques have been developed to monitor biomolecular assembly without the requirement for fluorophore marker molecules; in particular quartz crystal microbalance and surface plasmon resonance measurements provide advantageous alternatives to traditional spectroscopic methods and are currently receiving increasing attention in the context of amyloid growth assays.

Nilsson, K. Peter R.

doi: 10.1016/j.febslet.2009.04.016pmid: 19376114

Molecular probes for selective staining and imaging of protein aggregates, such as amyloid, are important to advance our understanding of the molecular mechanisms underlying protein misfolding diseases and also for obtaining an early and accurate clinical diagnosis of these disorders. Since normal immunohistochemical reagents, such as antibodies have shown limitation for identifying protein aggregates both in vitro and in vivo, small organic probes have been utilized as amyloid specific markers. In this review, past and recent molecular scaffolds that have been utilized for the development of small organic amyloid imaging agents are discussed.

Langkilde, Annette Eva; Vestergaard, Bente

doi: 10.1016/j.febslet.2009.05.040pmid: 19481541

Protein fibrillation is first and foremost a structural phenomenon. Adequate structural investigation of the central conformational individuals of the fibrillation process is however exceedingly difficult. This is due to the nature of the process, which may be described as a dynamically evolving equilibrium between a large number of structural species. These are furthermore of highly diverging sizes and present in very uneven amounts and timeframes. Different structural methods have different strengths and limitations. These, and in particular recent advances within solution analysis of the undisturbed equilibrium using small angle X‐ray scattering, are reviewed here.

Maji, Samir K.; Wang, Lei; Greenwald, Jason; Riek, Roland

doi: 10.1016/j.febslet.2009.07.003pmid: 19596006

Protein aggregation is a process in which proteins self‐associate into imperfectly ordered macroscopic entities. Such aggregates are generally classified as either amorphous or highly ordered, the most common form of the latter being amyloid fibrils. Amyloid fibrils composed of cross‐β‐sheet structure are the pathological hallmarks of several diseases including Alzheimer's disease, but are also associated with functional states such as the fungal HET‐s prion. This review aims to summarize the recent high‐resolution structural studies of amyloid fibrils in light of their (potential) activities. We propose that the repetitive nature of the cross‐β‐sheet structure of amyloids is key for their multiple properties: the repeating motifs can translate a rather non‐specific interaction into a specific one through cooperativity.

Baskakov, Ilia V.

doi: 10.1016/j.febslet.2009.05.044pmid: 19482025

Amyloid fibrils are highly ordered crystal‐like structures. It is generally assumed that individual amyloid fibrils consist of conformationally uniform cross‐β‐sheet structures that enable the amyloids to replicate their individual conformations via a template‐dependent mechanism. Recent studies revealed that amyloids are capable of accommodating a global conformational switch from one amyloid strain to another within individual fibrils. The current review highlights the high adaptation potential of amyloid structures and discusses the implication of these findings for several emerging issues including prion strain adaptation (i.e. gradual change in strain structure). It also proposes that the catalytic activity of an amyloid structure should be separated from its templating effect, and raises the question of strain classification according to their promiscuous or species‐specific nature.

Platt, Geoffrey W.; Radford, Sheena E.

doi: 10.1016/j.febslet.2009.05.005pmid: 19433089

β2‐microglobulin (β2m) is a 99‐residue protein that aggregates to form amyloid fibrils in dialysis‐related amyloidosis. The protein provides a powerful model for exploration of the structural molecular mechanisms of fibril formation from a full‐length protein in vitro. Fibrils have been assembled from β2m under both low pH conditions, where the precursor is disordered, and at neutral pH where the protein is initially natively folded. Here we discuss the roles of sequence and structure in amyloid formation, the current understanding of the structural mechanisms of the early stages of aggregation of β2m at both low and neutral pH, and the common and distinct features of these assembly pathways.

Bemporad, Francesco; Chiti, Fabrizio

doi: 10.1016/j.febslet.2009.07.013pmid: 19595999

Studies in vitro show that globular proteins can experience the formation of native‐like conformational states able to self‐assemble with no need of transitions across the energy barrier for unfolding, and that such processes can lead eventually to the formation of amyloid‐like species. Circumstantial evidence collected in vivo suggests that aggregation of native‐like states can be a concrete possibility for living organisms and thus more relevant than previously thought. In this review we summarize the key observations collected on the “native‐like aggregation” of the acylphosphatase from Sulfolobus solfataricus, a protein that has allowed the direct monitoring and analysis of native‐like aggregates for its propensity to form rapidly native‐like aggregates and their slow conversion into amyloid‐like aggregates.