Limits...
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.

Show MeSH

Related in: MedlinePlus

Hydrophobic residues in pWALTZ amyloid cores.The frequency of the indicated hydrophobic residues in pWALTZ amyloid cores relative to that in all the proteins in SwissProt is plotted for non-prion (red) and prion (white) domains. Positive and negative values correspond to overrepresented and underrepresented amino acids or amino acid groups, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4288708&req=5

pcbi-1004013-g005: Hydrophobic residues in pWALTZ amyloid cores.The frequency of the indicated hydrophobic residues in pWALTZ amyloid cores relative to that in all the proteins in SwissProt is plotted for non-prion (red) and prion (white) domains. Positive and negative values correspond to overrepresented and underrepresented amino acids or amino acid groups, respectively.

Mentions: The intriguing question thus remains of why PFDs are enriched in Q and especially in N and not in other residues with a higher hydrophobicity and/or β-sheet propensity, which would render them more amyloidogenic, as in typical amyloids. Together with their high Q/N content and their ability to form amyloid assemblies, an essential property of yeast PFD is that they lack regular secondary structure in their soluble state. It could be simply that Q and especially N constitute the most amyloidogenic residues that are still able to promote significant intrinsic disorder in a protein sequence. Not surprisingly, according to the FoldIndex algorithm [37] all the detected amyloid cores in prion domains are located in disordered protein regions. To test this possibility we constructed 21-mer homo-polymeric sequences for the 20 natural amino acids and analyzed their disorder and amyloidogenic propensity using Foldindex and pWALTZ simultaneously (Fig. 4). Interestingly enough, polyQ and specially polyN display both a high disorder and amyloidogenic propensity. Thus, Q and N enriched sequences would have a dual character that would allow them to maintain a certain amyloid potential and still remain disordered. However, polyQ and polyN render pWALTZ scores of 49.83 and 70.90, respectively, thus indicating that 21 residues core formed exclusively by these residues would not endorse prioneginicty to a sequence and therefore that the presence of hydrophobic residues in the core is a requirement for prion formation. The rest of predicted disordered sequences do not exhibit any amyloidogenic propensity according to pWALTZ, with the exception of polyY. Tyrosine is the most abundant hydrophobic residue in yeast PFDs [8]. We compared the composition of hydrophobic residues in the amyloid cores detected by pWALTZ in prionic and non-prionic sequences (Fig. 5) and found that non-aromatic hydrophobic residues are strongly underrepresented in both cores, relative to their average frequency in Swissprot [38], whereas aromatic residues are overrepresented in prionic cores and underrepresented in non-prionic ones, respectively. However, Tyr is the only residue that contributes to the overrepresentation of aromatic residues in prionic amyloid cores, being 2.7 times more abundant that the average in Swissprot (Fig. 5). It has been recently proposed that aromatic residues are favoured in PFD relative to non-aromatic hydrophobic residues, because they serve a dual function, promoting both prion formation and chaperone dependent prion propagation [39]. However, this does not explain why, despite differing in a single hydroxyl group, Tyr is much more prevalent than Phe at both the PFDs and their amyloid cores. A plausible reason for this bias is that Tyr displays a clearly higher amyloidogenicity/disorder ratio than Phe and the rest of hydrophobic residues, followed by Trp, which due to its size might cause steric hindrance in prion fibrillar structures, explaining its low abundance in PFDs [8]. Additionally, from the best scoring residues in the restrictive position 5 in the Waltz PSSM, Tyr is clearly superior in terms of disorder propensity, appearing thus as the best residue to endorse prionogenic Q/N rich amyloid cores with increased amyloid potential without disturbing significantly the PFDs disorder properties.


What makes a protein sequence a prion?

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

Hydrophobic residues in pWALTZ amyloid cores.The frequency of the indicated hydrophobic residues in pWALTZ amyloid cores relative to that in all the proteins in SwissProt is plotted for non-prion (red) and prion (white) domains. Positive and negative values correspond to overrepresented and underrepresented amino acids or amino acid groups, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1004013-g005: Hydrophobic residues in pWALTZ amyloid cores.The frequency of the indicated hydrophobic residues in pWALTZ amyloid cores relative to that in all the proteins in SwissProt is plotted for non-prion (red) and prion (white) domains. Positive and negative values correspond to overrepresented and underrepresented amino acids or amino acid groups, respectively.
Mentions: The intriguing question thus remains of why PFDs are enriched in Q and especially in N and not in other residues with a higher hydrophobicity and/or β-sheet propensity, which would render them more amyloidogenic, as in typical amyloids. Together with their high Q/N content and their ability to form amyloid assemblies, an essential property of yeast PFD is that they lack regular secondary structure in their soluble state. It could be simply that Q and especially N constitute the most amyloidogenic residues that are still able to promote significant intrinsic disorder in a protein sequence. Not surprisingly, according to the FoldIndex algorithm [37] all the detected amyloid cores in prion domains are located in disordered protein regions. To test this possibility we constructed 21-mer homo-polymeric sequences for the 20 natural amino acids and analyzed their disorder and amyloidogenic propensity using Foldindex and pWALTZ simultaneously (Fig. 4). Interestingly enough, polyQ and specially polyN display both a high disorder and amyloidogenic propensity. Thus, Q and N enriched sequences would have a dual character that would allow them to maintain a certain amyloid potential and still remain disordered. However, polyQ and polyN render pWALTZ scores of 49.83 and 70.90, respectively, thus indicating that 21 residues core formed exclusively by these residues would not endorse prioneginicty to a sequence and therefore that the presence of hydrophobic residues in the core is a requirement for prion formation. The rest of predicted disordered sequences do not exhibit any amyloidogenic propensity according to pWALTZ, with the exception of polyY. Tyrosine is the most abundant hydrophobic residue in yeast PFDs [8]. We compared the composition of hydrophobic residues in the amyloid cores detected by pWALTZ in prionic and non-prionic sequences (Fig. 5) and found that non-aromatic hydrophobic residues are strongly underrepresented in both cores, relative to their average frequency in Swissprot [38], whereas aromatic residues are overrepresented in prionic cores and underrepresented in non-prionic ones, respectively. However, Tyr is the only residue that contributes to the overrepresentation of aromatic residues in prionic amyloid cores, being 2.7 times more abundant that the average in Swissprot (Fig. 5). It has been recently proposed that aromatic residues are favoured in PFD relative to non-aromatic hydrophobic residues, because they serve a dual function, promoting both prion formation and chaperone dependent prion propagation [39]. However, this does not explain why, despite differing in a single hydroxyl group, Tyr is much more prevalent than Phe at both the PFDs and their amyloid cores. A plausible reason for this bias is that Tyr displays a clearly higher amyloidogenicity/disorder ratio than Phe and the rest of hydrophobic residues, followed by Trp, which due to its size might cause steric hindrance in prion fibrillar structures, explaining its low abundance in PFDs [8]. Additionally, from the best scoring residues in the restrictive position 5 in the Waltz PSSM, Tyr is clearly superior in terms of disorder propensity, appearing thus as the best residue to endorse prionogenic Q/N rich amyloid cores with increased amyloid potential without disturbing significantly the PFDs disorder properties.

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