The formation of spherulites by amyloid fibrils of bovine insulin

Krebs, Mark R.H.; MacPhee, Cait E.; Miller, Aline F.; Dunlop, Iain E.; Dobson, Christopher M.; Donald, Athene M.

doi:10.1073/pnas.0405933101

Cited by 235 publications

(311 citation statements)

References 48 publications

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“…In both settings, the molecular explanation for the Maltese cross is the formation of "spherulites", spherical aggregates emanating from a central growth point that appear to form under conditions of limited nucleation. Given the differences in chemical structure between proteins and synthetic polymers such as polypropylene, the resemblance of the spherulites in the EM is startling (Figure 7), suggestive of a deeper physical and structural resemblance of amyloid and synthetic polymers (37).…”

Section: Amyloid and Synthetic Polymers -Shared Features Shared Vocamentioning

confidence: 99%

Plasticity of Amyloid Fibrils

2006

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In experiments designed to characterize the basis of amyloid fibril stability through mutational analysis of the Aβ(1-40) molecule, fibrils exhibit consistent, significant structural malleability. In these results, and in other properties, amyloid fibrils appear to more resemble plastic materials generated from synthetic polymers than they do globular proteins. Thus, like synthetic polymers and plastics, amyloid fibrils exhibit both polymorphism, the ability of one polypeptide to form aggregates of different morphologies, and isomorphism, the ability of different polypeptides to grow into a fibrillar amyloid morphology. This view links amyloid with the prehistorical and 20 th Century use of proteins as starting materials to make films, fibers, and plastics, and with the classic protein fiber stretching experiments of the Astbury group. Viewing amyloid from the point of view of the polymer chemist may shed new light on issues such as the role of protofibrils in the mechanism of amyloid formation, the biological potency of fibrils, and the prospects for discovering inhibitors of amyloid fibril formation.Amyloid fibrils and amyloid-related protein aggregates are associated with a variety of human diseases of the brain and the periphery (1,2). The past decade has seen significant progress in our understanding of this alternatively folded protein structural motif. At the same time, much remains to be learned about details of amyloid structure, the basis of fibrillogenesis, and the nature of protein aggregate cytotoxicity.Experimental work over the past 10-15 years has revealed the amyloid folding motif to be a nearly ubiquitous alternative folded state that can be accessed by many polypeptides. For globular proteins, the route to amyloid often depends on initial weakening of the native state; in addition, for all proteins and peptides, amyloid formation also depends on packing constraints within the fibril (3). Reviewed here are mutagenesis experiments designed to focus on understanding the nature of the packing constraints within the amyloid motif.The results show that amyloid fibrils, like globular proteins, achieve stability through a mixture of hydrophobic and electrostatic forces. At the same time, the response of amyloid to mutagenesis differs in a number of ways from the typical response of globular proteins, and suggests instead a significant resemblance to synthetic polymers and plastics. A relationship to synthetic polymers provides a comfortable context for a number important features of amyloid fibrils, including: (a) the ability of so many naturally occurring proteins to form amyloid, (b) the observation of multiple conformational states of amyloid fibrils from the same polypeptide sequence, (c) the role of protofibrillar intermediates on the amyloid assembly pathway, (d) the biological potency of amyloid prions, and (e) the mixed success of attempts to identify inhibitors of the amyloid formation process. † Supported by NIH grant R01 AG018416 (RW). ‡ Present address:

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Section: Amyloid and Synthetic Polymers -Shared Features Shared Vocamentioning

confidence: 99%

Plasticity of Amyloid Fibrils

2006

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“…Possible mechanisms that prevent UPIa from leaving the ER include: (1) misfolding of luminal domains that are recognized by chaperones that form a part of the ER quality control system (Ellgaard and Helenius, 2003); (2) improper assembly of the TM domains (Cannon and Cresswell, 2001;Schamel et al, 2003;Swanton et al, 2003;Krebs et al, 2004;Kota and Ljungdahl, 2005); (3) lack of an ER exit signal (Barlowe, 2003); or (4) formation of large aggregates (Ellgaard and Helenius, 2003). We have performed experiments to define the roles of different domains of UPIb that allow it to exit from the ER, and to gain insight into the mechanisms involved in this process.…”

Section: Swapping Domains Of Upia and Upibmentioning

confidence: 99%

Integrity of all four transmembrane domains of the tetraspanin uroplakin Ib is required for its exit from the ER

Kong

Sun

et al. 2006

Journal of Cell Science

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“…The understanding of proliferation mechanisms is fundamental not only for material science applications, but also for biomedicine, which faces issues related to deposition and uncontrolled self-assembly of amyloids in the form of large plaques with dimensions on the order of micrometers. They result from a hierarchical organization that, from the atomistic level reaches the nanometer scale, where one or more fibrils arrange to form protofilaments [44][45][46] and the assembly of multiple protofilaments results in a variety of morphologies, including twisted rope-like structures, flat-tapes with nanometer-scale diameters [47,48], spherulitic structures [49] and, at a higher level of complexity, the characteristic amyloid plaques found in affected tissues.…”

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confidence: 99%

Failure of Aβ(1-40) amyloid fibrils under tensile loading

Paparcone

Buehler

2011

Biomaterials

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Amyloid fibrils and plaques are detected in the brain tissue of patients affected by Alzheimer's disease, but have also been found as part of normal physiological processes such as bacterial adhesion. Due to their highly organized structures, amyloid proteins have also been used for the development of novel nanomaterials, for a variety of applications including biomaterials for tissue engineering, nanolectronics, or optical devices. Past research on amyloid fibrils resulted in advances in identifying their mechanical properties, revealing a remarkable stiffness. However, the failure mechanism under tensile loading has not been elucidated yet, despite its importance for the understanding of key mechanical properties of amyloid fibrils and plaques as well as the growth and aggregation of amyloids into long fibers and plaques. Here we report a molecular level analysis of failure of amyloids under uniaxial tensile loading. Our molecular modeling results demonstrate that amyloid fibrils are extremely stiff with a Young's modulus in the range of 18-30 GPa, in good agreement with previous experimental and computational findings. The most important contribution of our study is our finding that amyloid fibrils fail at relatively small strains of 2.5% to 4%, and at stress levels in the range of 1.02 to 0.64 GPa, in good agreement with experimental findings. Notably, we find that the strength properties of amyloid fibrils are extremely length dependent, and that longer amyloid fibrils show drastically smaller failure strains and failure stresses. As a result, longer fibrils in excess of hundreds of nanometers to micrometers have a greatly enhanced propensity towards spontaneous fragmentation and failure. We use a combination of simulation results and simple theoretical models to define critical fibril lengths where distinct failure mechanisms dominate.

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The formation of spherulites by amyloid fibrils of bovine insulin

Cited by 235 publications

References 48 publications

Plasticity of Amyloid Fibrils

Plasticity of Amyloid Fibrils

Integrity of all four transmembrane domains of the tetraspanin uroplakin Ib is required for its exit from the ER

Failure of Aβ(1-40) amyloid fibrils under tensile loading

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