Entropic Bristles Tune the Seeding Efficiency of Prion-Nucleating Fragments

Michiels, Emiel; Liu, Shu; Gallardo, Rodrigo; Louros, Nikolaos; Mathelié‐Guinlet, Marion; Dufrêne, Yves F.; Schymkowitz, Joost; Vorberg, Ina; Rousseau, Frédéric

doi:10.1016/j.celrep.2020.01.098

Cited by 13 publications

(16 citation statements)

References 69 publications

(83 reference statements)

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“…This does not exclude modulating effects of other regions, even by regions that are not incorporated in the fibre core, such as the fuzzy coat observed in many amyloids 29 . However, by and large in disease amyloids assembly kinetics and stability are both would be sufficient to drive that process [35][36][37] .…”

Section: Discussionmentioning

confidence: 99%

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A structural analysis of amyloid polymorphism in disease: clues for selective vulnerability?

Kant

Louros

Schymkowitz

et al. 2021

Preprint

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The increasing amount of amyloid structures offers an opportunity to investigate the general principles determining amyloid stability and polymorphism in disease. We find that amyloid stability is dominated by about 30% of residues localized in few segments interspersed with regions that are often structurally frustrated in the cross-β conformation. These stable segments correspond to known aggregation-nucleating regions and constitute a cross-β structural framework that is shared among polymorphs. Alternative tertiary packing of these segments within the protofibril results in conformationally different but energetically similar polymorphs. This combination of a conserved structural framework along the axis and energetic ambiguity across the axis results in polymorphic plasticity that explains a number of fundamental amyloid properties, including fibril defects and brittleness but also the polymorphic instability of amyloids in simple aqueous buffers. Together these findings suggest a structural model for in vivo polymorphic bias and selective cellular vulnerability whereby (1) polymorphic bias is induced by particular templating interactions in susceptible cells, (2) once formed specific polymorphs are entropically primed to selectively bind similar targets in neighbouring cells, (3) conservation of polymorphic bias during pathological spreading implies the continued presence of similar templating interactions in successive susceptible cells and (4) absence of templating interactions relaxes polymorphic bias possibly allowing for the modification of cellular susceptibilities during disease progression by novel templating interactions.

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Section: Discussionmentioning

confidence: 99%

“…gatekeeper mutations at the flanks of APRs) together with mutations favouring more rapid alternative modes of assemblies (e.g. out of register β-sheet assembly) would be sufficient to drive that process 35-37 .…”

Section: Discussionmentioning

confidence: 99%

A structural analysis of amyloid polymorphism in disease: clues for selective vulnerability?

Kant

Louros

Schymkowitz

et al. 2021

Preprint

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“…The role of amino acid composition has also been indirectly expanded to regions flanking APRs in protein sequences. Our recent work has shown that single residues flanking APRs in protein sequences can act as gatekeepers that attenuate aggregation propensity [138,[163][164][165][166], whereas sequence stretches of high disorder can affect the transmissibility of functional prion APRs by modulating aggregation morphology [167].…”

Section: Is Sequence Specificity a Determining Factor In Amyloid Hetementioning

confidence: 99%

Heterotypic interactions in amyloid function and disease

et al. 2021

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Amyloid aggregation results from the self‐assembly of identical aggregation‐prone sequences into cross‐beta‐sheet structures. The process is best known for its association with a wide range of human pathologies but also as a functional mechanism in all kingdoms of life. Less well elucidated is the role of heterotypic interactions between amyloids and other proteins and macromolecules and how this contributes to disease. We here review current data with a focus on neurodegenerative amyloid‐associated diseases. Evidence indicates that heterotypic interactions occur in a wide range of amyloid processes and that these interactions modify fundamental aspects of amyloid aggregation including seeding, aggregation rates and toxicity. More work is required to understand the mechanistic origin of these interactions, but current understanding suggests that both supersaturation and sequence‐specific binding can contribute to heterotypic amyloid interactions. Further unravelling these mechanisms may help to answer outstanding questions in the field including the selective vulnerability of cells types and tissues and the stereotypical spreading patterns of amyloids in disease.

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“…Only when Doc binds and folds these IDP tails can operator binding proceed with high affinity and the phd/doc operon be repressed. This mechanism is further related to the action of entropic bristles, which are IDP tails that can act as solubilizers to prevent aggregation (Santner et al, 2012), tune prion nucleation (Michiels et al, 2020) and tune the energy landscape of proteins in general with respect to protein assemblies and ligand binding and association (Keul et al, 2018;Niemeyer et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Entropic pressure controls the oligomerization of the Vibrio cholerae ParD2 antitoxin

Garcia-Rodriguez

Girardin

Volkov

et al. 2021

Acta Cryst Sect D Struct Biol

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ParD2 is the antitoxin component of the parDE2 toxin–antitoxin module from Vibrio cholerae and consists of an ordered DNA-binding domain followed by an intrinsically disordered ParE-neutralizing domain. In the absence of the C-terminal intrinsically disordered protein (IDP) domain, V. cholerae ParD2 (VcParD2) crystallizes as a doughnut-shaped hexadecamer formed by the association of eight dimers. This assembly is stabilized via hydrogen bonds and salt bridges rather than by hydrophobic contacts. In solution, oligomerization of the full-length protein is restricted to a stable, open decamer or dodecamer, which is likely to be a consequence of entropic pressure from the IDP tails. The relative positioning of successive VcParD2 dimers mimics the arrangement of Streptococcus agalactiae CopG dimers on their operator and allows an extended operator to wrap around the VcParD2 oligomer.

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Entropic Bristles Tune the Seeding Efficiency of Prion-Nucleating Fragments

Cited by 13 publications

References 69 publications

A structural analysis of amyloid polymorphism in disease: clues for selective vulnerability?

A structural analysis of amyloid polymorphism in disease: clues for selective vulnerability?

Heterotypic interactions in amyloid function and disease

Entropic pressure controls the oligomerization of the Vibrio cholerae ParD2 antitoxin

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