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Comparing models of evolution for ordered and disordered proteins.

Brown CJ, Johnson AK, Daughdrill GW - Mol. Biol. Evol. (2009)

Bottom Line: Disordered proteins do not typically maintain long-range interactions, so the constraints on their evolution should be different than ordered proteins.Glutamic acid and asparagine were interesting exceptions to this result.Finally, the amino acid frequencies for disordered proteins, computed during the development of the matrices, were compared with amino acid frequencies for different categories of secondary structure in ordered proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, University of Idaho, USA. celesteb@uidaho.edu

ABSTRACT
Most models of protein evolution are based upon proteins that form relatively rigid 3D structures. A significant fraction of proteins, the so-called disordered proteins, do not form rigid 3D structures and sample a broad conformational ensemble. Disordered proteins do not typically maintain long-range interactions, so the constraints on their evolution should be different than ordered proteins. To test this hypothesis, we developed and compared models of evolution for disordered and ordered proteins. Substitution matrices were constructed using the sequences of putative homologs for sets of experimentally characterized disordered and ordered proteins. Separate matrices, at three levels of sequence similarity (>85%, 85-60%, and 60-40%), were inferred for each type of protein structure. The substitution matrices for disordered and ordered proteins differed significantly at each level of sequence similarity. The disordered matrices reflected a greater likelihood of evolutionary changes, relative to the ordered matrices, and these changes involved nonconservative substitutions. Glutamic acid and asparagine were interesting exceptions to this result. Important differences between the substitutions that are accepted in disordered proteins relative to ordered proteins were also identified. In general, disordered proteins have fewer evolutionary constraints than ordered proteins. However, some residues like tryptophan and tyrosine are highly conserved in disordered proteins. This is due to their important role in forming protein-protein interfaces. Finally, the amino acid frequencies for disordered proteins, computed during the development of the matrices, were compared with amino acid frequencies for different categories of secondary structure in ordered proteins. The highest correlations were observed between the amino acid frequencies in disordered proteins and the solvent-exposed loops and turns of ordered proteins, supporting an emerging structural model for disordered proteins.

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(A) Substitution matrices for ordered (O40, upper) and disordered (D40, lower) proteins at 40–60% sequence identity. Color shading indicates probability of substitutions being greater than expected by chance (blue) or less than expected (red). (B) Matrix showing the difference between D40 and O40. Color shading indicates greater frequency of substitutions in disorder (blue) or greater frequency in order (red). In all matrices, residues are ordered from most order promoting (green) to most disorder promoting (white) as shown in (Radivojac et al. 2007). D, disorder; O, order.
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fig3: (A) Substitution matrices for ordered (O40, upper) and disordered (D40, lower) proteins at 40–60% sequence identity. Color shading indicates probability of substitutions being greater than expected by chance (blue) or less than expected (red). (B) Matrix showing the difference between D40 and O40. Color shading indicates greater frequency of substitutions in disorder (blue) or greater frequency in order (red). In all matrices, residues are ordered from most order promoting (green) to most disorder promoting (white) as shown in (Radivojac et al. 2007). D, disorder; O, order.

Mentions: Figure 3A shows one-half of the symmetric substitution matrices for D40 (lower) and O40 (upper). The matrices are shaded to provide a quick visual reference of which amino acid substitutions are more or less likely. It is clear that the overall pattern of substitutions appears to be the same between the two structural types for many of the amino acid pairs. For instance, order-promoting amino acids are more likely to substitute with other order-promoting amino acids (shaded in dark green), and disorder-promoting amino acids are more likely to substitute with other disorder-promoting amino acids (shaded in white). Substitutions between order-promoting and disorder-promoting amino acids are less likely to occur for both matrices. There are some interesting exceptions to this observation. First, cysteine (C) has a far greater probability of substituting in disordered proteins than in ordered proteins. This is expected given the importance of C in forming disulfide bridges in ordered proteins and the lack of a similar function in disordered proteins. Second, and more unexpected, is the conserved nature of glutamic acid (E) especially relative to the less conserved, but biochemically similar, aspartic acid (D).


Comparing models of evolution for ordered and disordered proteins.

Brown CJ, Johnson AK, Daughdrill GW - Mol. Biol. Evol. (2009)

(A) Substitution matrices for ordered (O40, upper) and disordered (D40, lower) proteins at 40–60% sequence identity. Color shading indicates probability of substitutions being greater than expected by chance (blue) or less than expected (red). (B) Matrix showing the difference between D40 and O40. Color shading indicates greater frequency of substitutions in disorder (blue) or greater frequency in order (red). In all matrices, residues are ordered from most order promoting (green) to most disorder promoting (white) as shown in (Radivojac et al. 2007). D, disorder; O, order.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2822292&req=5

fig3: (A) Substitution matrices for ordered (O40, upper) and disordered (D40, lower) proteins at 40–60% sequence identity. Color shading indicates probability of substitutions being greater than expected by chance (blue) or less than expected (red). (B) Matrix showing the difference between D40 and O40. Color shading indicates greater frequency of substitutions in disorder (blue) or greater frequency in order (red). In all matrices, residues are ordered from most order promoting (green) to most disorder promoting (white) as shown in (Radivojac et al. 2007). D, disorder; O, order.
Mentions: Figure 3A shows one-half of the symmetric substitution matrices for D40 (lower) and O40 (upper). The matrices are shaded to provide a quick visual reference of which amino acid substitutions are more or less likely. It is clear that the overall pattern of substitutions appears to be the same between the two structural types for many of the amino acid pairs. For instance, order-promoting amino acids are more likely to substitute with other order-promoting amino acids (shaded in dark green), and disorder-promoting amino acids are more likely to substitute with other disorder-promoting amino acids (shaded in white). Substitutions between order-promoting and disorder-promoting amino acids are less likely to occur for both matrices. There are some interesting exceptions to this observation. First, cysteine (C) has a far greater probability of substituting in disordered proteins than in ordered proteins. This is expected given the importance of C in forming disulfide bridges in ordered proteins and the lack of a similar function in disordered proteins. Second, and more unexpected, is the conserved nature of glutamic acid (E) especially relative to the less conserved, but biochemically similar, aspartic acid (D).

Bottom Line: Disordered proteins do not typically maintain long-range interactions, so the constraints on their evolution should be different than ordered proteins.Glutamic acid and asparagine were interesting exceptions to this result.Finally, the amino acid frequencies for disordered proteins, computed during the development of the matrices, were compared with amino acid frequencies for different categories of secondary structure in ordered proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, University of Idaho, USA. celesteb@uidaho.edu

ABSTRACT
Most models of protein evolution are based upon proteins that form relatively rigid 3D structures. A significant fraction of proteins, the so-called disordered proteins, do not form rigid 3D structures and sample a broad conformational ensemble. Disordered proteins do not typically maintain long-range interactions, so the constraints on their evolution should be different than ordered proteins. To test this hypothesis, we developed and compared models of evolution for disordered and ordered proteins. Substitution matrices were constructed using the sequences of putative homologs for sets of experimentally characterized disordered and ordered proteins. Separate matrices, at three levels of sequence similarity (>85%, 85-60%, and 60-40%), were inferred for each type of protein structure. The substitution matrices for disordered and ordered proteins differed significantly at each level of sequence similarity. The disordered matrices reflected a greater likelihood of evolutionary changes, relative to the ordered matrices, and these changes involved nonconservative substitutions. Glutamic acid and asparagine were interesting exceptions to this result. Important differences between the substitutions that are accepted in disordered proteins relative to ordered proteins were also identified. In general, disordered proteins have fewer evolutionary constraints than ordered proteins. However, some residues like tryptophan and tyrosine are highly conserved in disordered proteins. This is due to their important role in forming protein-protein interfaces. Finally, the amino acid frequencies for disordered proteins, computed during the development of the matrices, were compared with amino acid frequencies for different categories of secondary structure in ordered proteins. The highest correlations were observed between the amino acid frequencies in disordered proteins and the solvent-exposed loops and turns of ordered proteins, supporting an emerging structural model for disordered proteins.

Show MeSH
Related in: MedlinePlus