Autonomous aggregation suppression by acidic residues explains why chaperones favour basic residues

Houben, Bert; Michiels, Emiel; Ramakers, Meine; Konstantoulea, Katerina; Louros, Nikolaos; Verniers, Joffré; Kant, Rob van der; Vleeschouwer, Matthias De; Chicória, Nuno; Vanpoucke, Thomas; Gallardo, Rodrigo; Schymkowitz, Joost; Rousseau, Frédéric

doi:10.15252/embj.2019102864

Cited by 36 publications

(39 citation statements)

References 60 publications

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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%

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%

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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“…Hydrophobic residues are often buried in the core of folded proteins, and hence the specificity of HSP70 for these residues might promote recognition of unfolded or newly synthesized proteins, enabling HSP70 to shield intermolecular interactions that might result in aggregation [100]. A recent study proposed that HSP70 prefers basic over acidic residues because basic residues are more compatible with globular structure, but make the protein depend on HSP70 to suppress aggregation [101]. In addition, others have suggested that the binding mechanism of HSP70 is flexible, allowing it to accommodate partially folded regions of proteins [102].…”

Section: Hsp70-type Chaperonesmentioning

confidence: 99%

Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome

et al. 2020

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Protein homeostasis (proteostasis) is essential for the cell and is maintained by a highly conserved protein quality control (PQC) system, which triages newly synthesized, mislocalized and misfolded proteins. The ubiquitin-proteasome system (UPS), molecular chaperones, and co-chaperones are vital PQC elements that work together to facilitate degradation of misfolded and toxic protein species through the 26S proteasome. However, the underlying mechanisms are complex and remain partly unclear. Here, we provide an overview of the current knowledge on the co-chaperones that directly take part in targeting and delivery of PQC substrates for degradation. While J-domain proteins (JDPs) target substrates for the heat shock protein 70 (HSP70) chaperones, nucleotide-exchange factors (NEFs) deliver HSP70-bound substrates to the proteasome. So far, three NEFs have been established in proteasomal delivery: HSP110 and the ubiquitin-like (UBL) domain proteins BAG-1 and BAG-6, the latter acting as a chaperone itself and carrying its substrates directly to the proteasome. A better understanding of the individual delivery pathways will improve our ability to regulate the triage, and thus regulate the fate of aberrant proteins involved in cell stress and disease, examples of which are given throughout the review.

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Autonomous aggregation suppression by acidic residues explains why chaperones favour basic residues

Cited by 36 publications

References 60 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

Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome

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