Limited Proteolysis Reveals That Amyloids from the 3D Domain-Swapping Cystatin B Have a Non-Native β-Sheet Topology

Davis, Peter J.; Holmes, David; Waltho, Jonathan P.; Staniforth, Rosemary A.

doi:10.1016/j.jmb.2015.05.014

Cited by 10 publications

(9 citation statements)

References 59 publications

(51 reference statements)

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“…In general, we can say that despite the small differences in the spine of fibrils that we offer for insulin and its analogues, using mass spectrometry it was not possible to identify sequences that can be interpreted as amyloidogenic in the local sites of the amino acid modifications of lispro and glargine. Some polymorphism in the sequences can be explained by the nonspecificity of the action of proteases, which was already noted in other works [65,66].…”

Section: Discussionsupporting

confidence: 62%

Determination of amyloid core regions of insulin analogues fibrils

Surin

Grishin

Galzitskaya

2020

Prion

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A rapid-acting insulin lispro and long-acting insulin glargine are commonly used for the treatment of diabetes. Clinical cases have described the formation of injectable amyloidosis with these insulin analogues, but their amyloid core regions of fibrils were unknown. To reveal these regions, we have analysed the hydrolyzates of insulin fibrils and its analogues using high-performance liquid chromatography and mass spectrometry methods and found that insulin and its analogues have almost identical amyloid core regions that intersect with the predicted amyloidogenic regions. The obtained results can be used to create new insulin analogues with a low ability to form fibrils. Abbreviations: a.a., amino acid residues; HPLC-MS, high-performance liquid chromatography/ mass spectrometry; m/z, mass-to-charge ratio; TEM, transmission electron microscopy.

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Section: Discussionsupporting

confidence: 62%

Determination of amyloid core regions of insulin analogues fibrils

Surin

Grishin

Galzitskaya

2020

Prion

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“…However, the propagated domain-swapping mechanism has been challenged recently (25,65). For example, cystatin B, a close relative of CysC, is known to dimerize by domain-swapping but forms fibrils that are structurally inconsistent with propagated domain-swapping (26).…”

Section: Discussionmentioning

confidence: 99%

“…It has been proposed that CysC amyloid fibrils form via propagated domain-swapping ( Fig. 1c) (15,21,23,24), although this view has been challenged recently (25,26).…”

mentioning

confidence: 99%

Insights into the mechanism of cystatin C oligomer and amyloid formation and its interaction with β-amyloid

Perlenfein

Mehlhoff

Murphy

2017

Journal of Biological Chemistry

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Cystatin C (CysC) is a versatile and ubiquitously-expressed member of the cysteine protease inhibitor family that is present at notably high concentrations in cerebrospinal fluid. Under mildly denaturing conditions, CysC forms inactive domain-swapped dimers. A destabilizing mutation, L68Q, increases the rate of domain-swapping and causes a fatal amyloid disease, hereditary cystatin C amyloid angiopathy. Wild-type (wt) CysC will also aggregate into amyloid fibrils under some conditions. Propagated domain-swapping has been proposed as the mechanism by which CysC fibrils grow. We present evidence that a CysC mutant, V57N, stabilized against domain-swapping, readily forms fibrils, contradicting the propagated domain-swapping hypothesis. Furthermore, in physiological buffer, wt CysC can form oligomers without undergoing domain-swapping. These non-swapped oligomers are identical in secondary structure to CysC monomers and completely retain protease inhibitory activity. However, unlike monomers or dimers, the oligomers bind fluorescent dyes that indicate they have characteristics of pre-amyloid aggregates. Although these oligomers appear to be a pre-amyloid assembly, they are slower than CysC monomers to form fibrils. Fibrillation of CysC therefore likely initiates from the monomer and does not require domain-swapping. The non-swapped oligomers likely represent a dead-end offshoot of the amyloid pathway and must dissociate to monomers prior to rearranging to amyloid fibrils. These prefibrillar CysC oligomers were potent inhibitors of aggregation of the Alzheimer's-related peptide, β-amyloid. This result illustrates an example where heterotypic interactions between pre-amyloid oligomers prevent the homotypic interactions that would lead to mature amyloid fibrils.

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“…At the secondary structure level, these oligomers have often been found to incorporate at least some b-sheets, and in many (although not all) cases arrangement of b-strands into b-sheets in oligomers was found to be antiparallel [14][15][16][17][18]. This is distinct from amyloid fibrils where, with a few exceptions, b-sheet arrangement was found to be parallel [19][20][21]. Examples of amyloid oligomer structures found in different proteins are discussed below.…”

Section: Secondary and Tertiary Structurementioning

confidence: 99%

Structural, morphological, and functional diversity of amyloid oligomers

2015

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a b s t r a c tProtein misfolding and aggregation are known to play a crucial role in a number of important human diseases (Alzheimer's, Parkinson's, prion, diabetes, cataracts, etc.) as well as in a multitude of physiological processes. Protein aggregation is a highly complex process resulting in a variety of aggregates with different structures and morphologies. Oligomeric protein aggregates (amyloid oligomers) are formed as both intermediates and final products of the aggregation process. They are believed to play an important role in many protein aggregation-related diseases, and many of them are highly cytotoxic. Due to their instability and structural heterogeneity, information about structure, mechanism of formation, and physiological effects of amyloid oligomers is sparse. This review attempts to summarize the existing information on the major properties of amyloid oligomers.

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Limited Proteolysis Reveals That Amyloids from the 3D Domain-Swapping Cystatin B Have a Non-Native β-Sheet Topology

Cited by 10 publications

References 59 publications

Determination of amyloid core regions of insulin analogues fibrils

Determination of amyloid core regions of insulin analogues fibrils

Insights into the mechanism of cystatin C oligomer and amyloid formation and its interaction with β-amyloid

Structural, morphological, and functional diversity of amyloid oligomers

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