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What makes a protein sequence a prion?

Sabate R, Rousseau F, Schymkowitz J, Ventura S - PLoS Comput. Biol. (2015)

Bottom Line: In many cases, prion structural conversion is driven by the presence of relatively large glutamine/asparagine (Q/N) enriched segments.Several studies suggest that it is the amino acid composition of these regions rather than their specific sequence that accounts for their priogenicity.However, our analysis indicates that it is instead the presence and potency of specific short amyloid-prone sequences that occur within intrinsically disordered Q/N-rich regions that determine their prion behaviour, modulated by the structural and compositional context.

View Article: PubMed Central - PubMed

Affiliation: Departament de Fisicoquímica, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain; Institut de Nanociència i Nanotecnologia (IN2UB), Universitat de Barcelona, Barcelona, Spain.

ABSTRACT
Typical amyloid diseases such as Alzheimer's and Parkinson's were thought to exclusively result from de novo aggregation, but recently it was shown that amyloids formed in one cell can cross-seed aggregation in other cells, following a prion-like mechanism. Despite the large experimental effort devoted to understanding the phenomenon of prion transmissibility, it is still poorly understood how this property is encoded in the primary sequence. In many cases, prion structural conversion is driven by the presence of relatively large glutamine/asparagine (Q/N) enriched segments. Several studies suggest that it is the amino acid composition of these regions rather than their specific sequence that accounts for their priogenicity. However, our analysis indicates that it is instead the presence and potency of specific short amyloid-prone sequences that occur within intrinsically disordered Q/N-rich regions that determine their prion behaviour, modulated by the structural and compositional context. This provides a basis for the accurate identification and evaluation of prion candidate sequences in proteomes in the context of a unified framework for amyloid formation and prion propagation.

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Alternative models for amyloid formation in prion-like domains.The compositional model relies on the establishment a large number of weak interactions whereas the pWALTZ model suggests a preferential nucleation by a short amyloidogenic stretch, whose amyloid propensity is modulated by the structural context.
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pcbi-1004013-g006: Alternative models for amyloid formation in prion-like domains.The compositional model relies on the establishment a large number of weak interactions whereas the pWALTZ model suggests a preferential nucleation by a short amyloidogenic stretch, whose amyloid propensity is modulated by the structural context.

Mentions: The results in the present study together with several lines of evidence from the literature indicate that for a protein sequence to become a prion domain it requires: i) a specific region with significant amyloid propensity able to selectively nucleate the self-assembly into ordered, but brittle, amyloid structures ii) a disordered structural context that, in contrast to what happens in structured globular proteins, readily permits the domain self-assembly without a requirement for conformational unfolding, and iii) an amino acid composition that while allowing the domain to be soluble at the physiological concentrations required for the normal protein function still display a basal amyloid propensity, to which N residues would contribute significantly, promoting their self assembly in the presence of preformed amyloid seeds or when its concentration is increased. All these prion properties are readily predictable, opening an avenue for the accurate identification of prionic sequences in proteomes. Moreover, because aggregation of human PFD containing proteins might contribute to the etiology of a number of degenerative diseases, the present approach might find application in the detection of pathogenic genetic mutations associated with these disorders. Composition based methods provide good prion prediction accuracies by assuming that in these particular proteins amyloid formation relies on the establishment a large number of weak interactions between side-chains in long disordered domains (Fig. 6), but in fact they mask the presence of specific short sequence stretches that, as in other amyloids, would trigger the conversion of prions from the soluble to the aggregated and transmissible state (Fig. 6). Instead of two contrasting views, our analysis suggests a model for Q/N rich prions, where a classical amyloid core is embedded in a compositional context that reduces the amyloid nucleation potential, giving rise to sequences that are strongly dependent on seeding.


What makes a protein sequence a prion?

Sabate R, Rousseau F, Schymkowitz J, Ventura S - PLoS Comput. Biol. (2015)

Alternative models for amyloid formation in prion-like domains.The compositional model relies on the establishment a large number of weak interactions whereas the pWALTZ model suggests a preferential nucleation by a short amyloidogenic stretch, whose amyloid propensity is modulated by the structural context.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4288708&req=5

pcbi-1004013-g006: Alternative models for amyloid formation in prion-like domains.The compositional model relies on the establishment a large number of weak interactions whereas the pWALTZ model suggests a preferential nucleation by a short amyloidogenic stretch, whose amyloid propensity is modulated by the structural context.
Mentions: The results in the present study together with several lines of evidence from the literature indicate that for a protein sequence to become a prion domain it requires: i) a specific region with significant amyloid propensity able to selectively nucleate the self-assembly into ordered, but brittle, amyloid structures ii) a disordered structural context that, in contrast to what happens in structured globular proteins, readily permits the domain self-assembly without a requirement for conformational unfolding, and iii) an amino acid composition that while allowing the domain to be soluble at the physiological concentrations required for the normal protein function still display a basal amyloid propensity, to which N residues would contribute significantly, promoting their self assembly in the presence of preformed amyloid seeds or when its concentration is increased. All these prion properties are readily predictable, opening an avenue for the accurate identification of prionic sequences in proteomes. Moreover, because aggregation of human PFD containing proteins might contribute to the etiology of a number of degenerative diseases, the present approach might find application in the detection of pathogenic genetic mutations associated with these disorders. Composition based methods provide good prion prediction accuracies by assuming that in these particular proteins amyloid formation relies on the establishment a large number of weak interactions between side-chains in long disordered domains (Fig. 6), but in fact they mask the presence of specific short sequence stretches that, as in other amyloids, would trigger the conversion of prions from the soluble to the aggregated and transmissible state (Fig. 6). Instead of two contrasting views, our analysis suggests a model for Q/N rich prions, where a classical amyloid core is embedded in a compositional context that reduces the amyloid nucleation potential, giving rise to sequences that are strongly dependent on seeding.

Bottom Line: In many cases, prion structural conversion is driven by the presence of relatively large glutamine/asparagine (Q/N) enriched segments.Several studies suggest that it is the amino acid composition of these regions rather than their specific sequence that accounts for their priogenicity.However, our analysis indicates that it is instead the presence and potency of specific short amyloid-prone sequences that occur within intrinsically disordered Q/N-rich regions that determine their prion behaviour, modulated by the structural and compositional context.

View Article: PubMed Central - PubMed

Affiliation: Departament de Fisicoquímica, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain; Institut de Nanociència i Nanotecnologia (IN2UB), Universitat de Barcelona, Barcelona, Spain.

ABSTRACT
Typical amyloid diseases such as Alzheimer's and Parkinson's were thought to exclusively result from de novo aggregation, but recently it was shown that amyloids formed in one cell can cross-seed aggregation in other cells, following a prion-like mechanism. Despite the large experimental effort devoted to understanding the phenomenon of prion transmissibility, it is still poorly understood how this property is encoded in the primary sequence. In many cases, prion structural conversion is driven by the presence of relatively large glutamine/asparagine (Q/N) enriched segments. Several studies suggest that it is the amino acid composition of these regions rather than their specific sequence that accounts for their priogenicity. However, our analysis indicates that it is instead the presence and potency of specific short amyloid-prone sequences that occur within intrinsically disordered Q/N-rich regions that determine their prion behaviour, modulated by the structural and compositional context. This provides a basis for the accurate identification and evaluation of prion candidate sequences in proteomes in the context of a unified framework for amyloid formation and prion propagation.

Show MeSH
Related in: MedlinePlus