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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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Residues that are most conserved are different between disordered and ordered proteins, and conservation is not determined by frequency. (A) Differences between the probability that an amino acid is conserved at a site (pii) for disorder and order at 40–60% identity for each of the 20 amino acids (i). Error bars indicate one standard deviation. (B) Scatter plot of the frequencies of each amino acid versus pii for disorder (filled diamonds) and order (open squares) at 40–60% identity.
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fig4: Residues that are most conserved are different between disordered and ordered proteins, and conservation is not determined by frequency. (A) Differences between the probability that an amino acid is conserved at a site (pii) for disorder and order at 40–60% identity for each of the 20 amino acids (i). Error bars indicate one standard deviation. (B) Scatter plot of the frequencies of each amino acid versus pii for disorder (filled diamonds) and order (open squares) at 40–60% identity.

Mentions: Figure 4A shows the differences in amino acid conservation between the D40 and O40 matrices by comparing their diagonal probabilities, pii. Values >0 indicate that an amino acid is more conserved in D40 than in O40. It is not surprising that cysteine (C) is more conserved in ordered proteins than in disordered proteins because it often forms long-range covalent bonds that stabilize the folded protein. It was surprising to find that several amino acids, including glutamic acid (E) and asparagine (N), were more conserved in disordered proteins than in ordered proteins. Because C is more frequent in ordered proteins, and E and N are more frequent in disordered proteins at this percent identity, we checked to see if there was a correlation between the probability that an amino acid is conserved and the frequency of each amino acid (fig. 4B). Excluding glycine (G), which is a clear outlier in this graph, there is no correlation between pii and pi for either the disordered or ordered matrices.


Comparing models of evolution for ordered and disordered proteins.

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

Residues that are most conserved are different between disordered and ordered proteins, and conservation is not determined by frequency. (A) Differences between the probability that an amino acid is conserved at a site (pii) for disorder and order at 40–60% identity for each of the 20 amino acids (i). Error bars indicate one standard deviation. (B) Scatter plot of the frequencies of each amino acid versus pii for disorder (filled diamonds) and order (open squares) at 40–60% identity.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: Residues that are most conserved are different between disordered and ordered proteins, and conservation is not determined by frequency. (A) Differences between the probability that an amino acid is conserved at a site (pii) for disorder and order at 40–60% identity for each of the 20 amino acids (i). Error bars indicate one standard deviation. (B) Scatter plot of the frequencies of each amino acid versus pii for disorder (filled diamonds) and order (open squares) at 40–60% identity.
Mentions: Figure 4A shows the differences in amino acid conservation between the D40 and O40 matrices by comparing their diagonal probabilities, pii. Values >0 indicate that an amino acid is more conserved in D40 than in O40. It is not surprising that cysteine (C) is more conserved in ordered proteins than in disordered proteins because it often forms long-range covalent bonds that stabilize the folded protein. It was surprising to find that several amino acids, including glutamic acid (E) and asparagine (N), were more conserved in disordered proteins than in ordered proteins. Because C is more frequent in ordered proteins, and E and N are more frequent in disordered proteins at this percent identity, we checked to see if there was a correlation between the probability that an amino acid is conserved and the frequency of each amino acid (fig. 4B). Excluding glycine (G), which is a clear outlier in this graph, there is no correlation between pii and pi for either the disordered or ordered matrices.

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