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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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Related in: MedlinePlus

Amyloid propensities of Q and N residues in the context natural yeast prions.pWALTZ scores of wild-type (WT) (pink) and virtual mutants in which all Q residues are changed to N (red) or all N residues into Q (white) in the PrD of natural yeast prions.
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pcbi-1004013-g003: Amyloid propensities of Q and N residues in the context natural yeast prions.pWALTZ scores of wild-type (WT) (pink) and virtual mutants in which all Q residues are changed to N (red) or all N residues into Q (white) in the PrD of natural yeast prions.

Mentions: A surprising finding in Alberti's study is that, despite differing only in a methylene group, the ratio of N to Q residues is an important determinant of the prion propensity of a sequence. Prionic domains are, as a trend, enriched in N whereas Q are more abundant in non-prionic sequences in their dataset [15]. Since according to our analysis amyloidogenicity seems to contribute significantly to prion-forming capability, it could be simply that N residues are more amyloidogenic than Q in the context of prion sequences, in agreement with the observation that according to the WALTZ PSSM, N is tolerated in more positions than Q in amyloid sequences (S1 Fig). Interestingly, the 21 residues long amyloid cores detected by pWALTZ in prionic sequences in our dataset contain an average of 9.9 N and 1.3 Q residues, whereas the equivalent sequence stretches in non-prionic sequences contain 4.1 N and 6.0 Q residues, respectively. Therefore, despite in both cases Q+N account for ∼1/2 of the residues in the core, amyloid cores in prionic domains are highly enriched in N residues, with a N/Q ratio of 7.9, whereas non-prionic cores display a N/Q ratio of only 0.7 at their cores. This suggests that despite their similar physicochemical properties these two residues endorse sequences with different amyloidogenic potential. Consistently, when we compared the predicted amyloidogenicity of known yeast PFD and of virtual mutants in which all N were replaced by Q and vice versa using pWALTZ, we found that, as a trend, the N to Q replacement decreases the amyloid propensity of the domains, whereas changing Q into N results in propensities similar that of the wild type sequence, when the core is already enriched in N residues, or increases the amyloid propensity of the domain (Fig. 3). These observations are in excellent agreement with the recent experimental demonstration by the Lindquist's group that N richness promotes assembly of self-templating amyloids whereas Q richness favours the formation of non-amyloid conformers [36].


What makes a protein sequence a prion?

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

Amyloid propensities of Q and N residues in the context natural yeast prions.pWALTZ scores of wild-type (WT) (pink) and virtual mutants in which all Q residues are changed to N (red) or all N residues into Q (white) in the PrD of natural yeast prions.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1004013-g003: Amyloid propensities of Q and N residues in the context natural yeast prions.pWALTZ scores of wild-type (WT) (pink) and virtual mutants in which all Q residues are changed to N (red) or all N residues into Q (white) in the PrD of natural yeast prions.
Mentions: A surprising finding in Alberti's study is that, despite differing only in a methylene group, the ratio of N to Q residues is an important determinant of the prion propensity of a sequence. Prionic domains are, as a trend, enriched in N whereas Q are more abundant in non-prionic sequences in their dataset [15]. Since according to our analysis amyloidogenicity seems to contribute significantly to prion-forming capability, it could be simply that N residues are more amyloidogenic than Q in the context of prion sequences, in agreement with the observation that according to the WALTZ PSSM, N is tolerated in more positions than Q in amyloid sequences (S1 Fig). Interestingly, the 21 residues long amyloid cores detected by pWALTZ in prionic sequences in our dataset contain an average of 9.9 N and 1.3 Q residues, whereas the equivalent sequence stretches in non-prionic sequences contain 4.1 N and 6.0 Q residues, respectively. Therefore, despite in both cases Q+N account for ∼1/2 of the residues in the core, amyloid cores in prionic domains are highly enriched in N residues, with a N/Q ratio of 7.9, whereas non-prionic cores display a N/Q ratio of only 0.7 at their cores. This suggests that despite their similar physicochemical properties these two residues endorse sequences with different amyloidogenic potential. Consistently, when we compared the predicted amyloidogenicity of known yeast PFD and of virtual mutants in which all N were replaced by Q and vice versa using pWALTZ, we found that, as a trend, the N to Q replacement decreases the amyloid propensity of the domains, whereas changing Q into N results in propensities similar that of the wild type sequence, when the core is already enriched in N residues, or increases the amyloid propensity of the domain (Fig. 3). These observations are in excellent agreement with the recent experimental demonstration by the Lindquist's group that N richness promotes assembly of self-templating amyloids whereas Q richness favours the formation of non-amyloid conformers [36].

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