Runaway domain swapping in amyloid-like fibrils of T7 endonuclease I

Guo, Zhefeng; Eisenberg, David

doi:10.1073/pnas.0602607103

Cited by 88 publications

(101 citation statements)

References 44 publications

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“…To create contact, and thus binding energy between the two wrapped protofilaments, we introduce runaway domain swapping interactions that join the two protofilaments at the seams created by the protofilament edges. Runaway swapping interactions have been observed in fiber assembly (37)(38)(39). A TABFO model with runaway domain swapping is shown schematically in Fig.…”

Section: Resultsmentioning

confidence: 99%

Toxic fibrillar oligomers of amyloid-β have cross-β structure

Stroud

Liu

Teng

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Although amyloid fibers are found in neurodegenerative diseases, evidence points to soluble oligomers of amyloid-forming proteins as the cytotoxic species. Here, we establish that our preparation of toxic amyloid-β 1-42 (Abeta42) fibrillar oligomers (TABFOs) shares with mature amyloid fibrils the cross-β structure, in which adjacent β-sheets adhere by interpenetration of protein side chains. We study the structure and properties of TABFOs by powder X-ray diffraction, EM, circular dichroism, FTIR spectroscopy, chromatography, conformational antibodies, and celluar toxicity. In TABFOs, Abeta42 molecules stack into short protofilaments consisting of pairs of helical β-sheets that wrap around each other to form a superhelix. Wrapping results in a hole along the superhelix axis, providing insight into how Abeta may form pathogenic amyloid pores. Our model is consistent with numerous properties of Abeta42 fibrillar oligomers, including heterogenous size, ability to seed new populations of fibrillar oligomers, and fiber-like morphology.Abeta oligomers | toxic oligomers | Alzheimer's disease | domain swapping | protein aggregation S everal neurodegenerative diseases are correlated with amyloid fibrillar deposits (1). For a number of these diseases, it has been postulated that amyloid fibers may not play the primary causative role (2). Rather, soluble aggregates of the amyloidogenic proteins are likely the relevant etiological agents (2, 3). The most prevalent of these neurodegenerative diseases, Alzheimer's disease (4), is strongly linked to the presence of soluble aggregates of amyloid-β (Abeta) (5). Abeta aggregates have been shown to impair neurite function (6), synaptic morphology (7), cognitive function (8), and cell viability (9). In the prion conditions, also classed as amyloid diseases (10), small oligomers have also been identified as the toxic species (11). Recently, the availability of structure-specific antibodies has provided a means to group oligomers into two broad antigenic categories known as prefibrillar and fibrillar oligomers (12). Fibrillar oligomers are recognized by the OC antibody isolated from rabbits immunized with Abeta fibers (13), suggesting that Abeta fibrillar oligomers share surface features with Abeta fibers. In addition to fiber-like morphology, fibrillar oligomers are similar to fibers in that fibrillar oligomers can seed new populations of fibrillar oligomers (14). The ability to seed suggests that, like fibers, fibrillar oligomers are organized into a repeating array or lattice of monomers, wherein the monomers have identical structures. Fibrillar oligomers likely have a distinct lattice from fibers, because Abeta fibrillar oligomers do not seed Abeta fiber formation (14). Here, we characterize a particular preparation of fibrillar oligomers that we term toxic Abeta 1-42 (Abeta42) fibrillar oligomers (TABFOs).The structure of amyloid fibers may provide insight into the structure of fibrillar oligomers. Fiber diffraction studies of chemically pure amyloid display a cross-β diffraction...

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Section: Resultsmentioning

confidence: 99%

Toxic fibrillar oligomers of amyloid-β have cross-β structure

Stroud

Liu

Teng

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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301

273

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“…The creation of higher order oligomers through domain swapping has been found to play multiple roles in vivo. Domain-swapped proteins have been shown to form amyloid-like fibrils, 38 which has led to the proposal that deposition diseases that involve protein aggregation, e.g. Alzheimer's and Parkinson's, may involve runaway domain swapping.…”

Section: Discussionmentioning

confidence: 99%

The crystal structure of the mycobacterium tuberculosis Rv3019c‐Rv3020c ESX complex reveals a domain‐swapped heterotetramer

Arbing¹,

Kaufmann²,

Phan³

et al. 2010

Protein Science

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Mycobacterium tuberculosis encodes five gene clusters (ESX-1 to ESX-5) for Type VII protein secretion systems that are implicated in mycobacterial pathogenicity. Substrates for the secretion apparatus are encoded within the gene clusters and in additional loci that lack the components of the secretion apparatus. The best characterized substrates are the ESX complexes, 1:1 heterodimers of ESAT-6 and CFP-10, the prototypical member that has been shown to be essential for Mycobacterium tuberculosis pathogenesis. We have determined the structure of EsxRS, a homolog of EsxGH of the ESX-3 gene cluster, at 1.91 Å resolution. The EsxRS structure is composed of two four-helix bundles resulting from the 3D domain swapping of the C-terminal domain of EsxS, the CFP-10 homolog. The four-helix bundles at the extremities of the complex have a similar architecture to the structure of ESAT-6ÁCFP-10 (EsxAB) of ESX-1, but in EsxRS a hinge loop linking the a-helical domains of EsxS undergoes a loop-to-helix transition that creates the domain swapped EsxRS tetramer. Based on the atomic structure of EsxRS and existing biochemical data on ESX complexes, we propose that higher order ESX oligomers may increase avidity of ESX binding to host receptor molecules or, alternatively, the conformational change that creates the domain swapped structure may be the basis of ESX complex dissociation that would free ESAT-6 to exert a cytotoxic effect.

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“…1C) (10,15,22,27,44). A recent study of in vitro fibrillization of a variant of T7 endonuclease has provided experimental evidence of propagated domain swapping as a mechanism in the formation of amyloid-like fibrils (25). To investigate a possible role of propagated three-dimensional domain swapping in the formation of cystatin C oligomers, redox experiments have been performed using stabilized wt cystatin C variants.…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that the process of three-dimensional domain swapping, when propagated in an open-ended fashion, could be the basis of the formation of amyloid fibrils (22)(23)(24)(25)(26)(27). We have earlier reported on stabilized variants of monomeric wt and L68Q cystatin C, with cysteine mutations introduced for selective formation of disulfide bridges between the tertiary structure elements that undergo separation on domain swapping (Fig.…”

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confidence: 99%

Fibrillogenic Oligomers of Human Cystatin C Are Formed by Propagated Domain Swapping

Wahlbom

Wang

Lindström

et al. 2007

Journal of Biological Chemistry

116

132

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Cystatin C and the prion protein have been shown to form dimers via three-dimensional domain swapping, and this process has also been hypothesized to be involved in amyloidogenesis. Production of oligomers of other amyloidogenic proteins has been reported to precede fibril formation, suggesting oligomers as intermediates in fibrillogenesis. A variant of cystatin C, with a Leu 68 3 Gln substitution, is highly amyloidogenic, and carriers of this mutation suffer from massive cerebral amyloidosis leading to brain hemorrhage and death in early adulthood. This work describes doughnut-shaped oligomers formed by wild type and L68Q cystatin C upon incubation of the monomeric proteins. Purified oligomers of cystatin C are shown to fibrillize faster and at a lower concentration than the monomeric protein, indicating a role of the oligomers as fibril-assembly intermediates. Moreover, the present work demonstrates that three-dimensional domain swapping is involved in the formation of the oligomers, because variants of monomeric cystatin C, stabilized against three-dimensional domain swapping by engineered disulfide bonds, do not produce oligomers upon incubation under non-reducing conditions. Redox experiments using wild type and stabilized cystatin C strongly suggest that the oligomers, and thus probably the fibrils as well, are formed by propagated domain swapping rather than by assembly of domain-swapped cystatin C dimers.

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Runaway domain swapping in amyloid-like fibrils of T7 endonuclease I

Cited by 88 publications

References 44 publications

Toxic fibrillar oligomers of amyloid-β have cross-β structure

Toxic fibrillar oligomers of amyloid-β have cross-β structure

The crystal structure of the mycobacterium tuberculosis Rv3019c‐Rv3020c ESX complex reveals a domain‐swapped heterotetramer

Fibrillogenic Oligomers of Human Cystatin C Are Formed by Propagated Domain Swapping

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