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The evolution of protein structures and structural ensembles under functional constraint.

Siltberg-Liberles J, Grahnen JA, Liberles DA - Genes (Basel) (2011)

Bottom Line: This ties back to a question of the role of neostructuralization and how it relates to selection on sequences for functions.The relationship between metastability, the fitness landscape, sequence divergence, and organismal effective population size is explored.Lastly, a brief discussion of modeling the evolution of sequences of ordered and disordered proteins is entertained.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, University of Wyoming, Laramie, WY 82071, USA. jliberle@uwyo.edu.

ABSTRACT
Protein sequence, structure, and function are inherently linked through evolution and population genetics. Our knowledge of protein structure comes from solved structures in the Protein Data Bank (PDB), our knowledge of sequence through sequences found in the NCBI sequence databases (http://www.ncbi.nlm.nih.gov/), and our knowledge of function through a limited set of in-vitro biochemical studies. How these intersect through evolution is described in the first part of the review. In the second part, our understanding of a series of questions is addressed. This includes how sequences evolve within structures, how evolutionary processes enable structural transitions, how the folding process can change through evolution and what the fitness impacts of this might be. Moving beyond static structures, the evolution of protein kinetics (including normal modes) is discussed, as is the evolution of conformational ensembles and structurally disordered proteins. This ties back to a question of the role of neostructuralization and how it relates to selection on sequences for functions. The relationship between metastability, the fitness landscape, sequence divergence, and organismal effective population size is explored. Lastly, a brief discussion of modeling the evolution of sequences of ordered and disordered proteins is entertained.

No MeSH data available.


Evolution of an energy landscape and its conformational ensemble after gene duplication. At the root, the gene giving rise to the protein with the blue energy landscape resulting in conformations A to G is duplicated. At the next speciation event we can see that the two different gene copies have evolved along different trajectories. The blue copy at the speciation node has evolved under negative selection and resembles the ancient blue. The green copy at the speciation node has evolved under positive selection and of the original conformational ensemble, conformations F and G are no longer forming, but a new conformation, H, is forming. In addition, the equilibrium of the conformations is different in the blue vs. green energy landscapes. From the speciation node down to the extant sequences, blue is much conserved, while green although under negative selection, will lose conformation D, in one lineage. Analysis of the extant sequences would show that blue and green are structurally disordered homologs. However, although all these proteins are structurally disordered, the conformational ensembles differ between blue and green (while being the same within the blue copies, and very similar within the green copies.)
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f2-genes-02-00748: Evolution of an energy landscape and its conformational ensemble after gene duplication. At the root, the gene giving rise to the protein with the blue energy landscape resulting in conformations A to G is duplicated. At the next speciation event we can see that the two different gene copies have evolved along different trajectories. The blue copy at the speciation node has evolved under negative selection and resembles the ancient blue. The green copy at the speciation node has evolved under positive selection and of the original conformational ensemble, conformations F and G are no longer forming, but a new conformation, H, is forming. In addition, the equilibrium of the conformations is different in the blue vs. green energy landscapes. From the speciation node down to the extant sequences, blue is much conserved, while green although under negative selection, will lose conformation D, in one lineage. Analysis of the extant sequences would show that blue and green are structurally disordered homologs. However, although all these proteins are structurally disordered, the conformational ensembles differ between blue and green (while being the same within the blue copies, and very similar within the green copies.)

Mentions: One of the mechanisms for generating novel or partitioned functions is through gene duplications/gene redundancy. It was recently shown that gene retention after gene duplication is higher for genes with many phosphorylation sites [71]. Structurally disordered proteins are enriched in phosphorylation sites and perhaps the thermodynamics of disorder in itself can provide an explanation. For globular structured proteins one main determinant for fixing a mutation is the effect of the mutation on the stability of the protein fold. Structurally disordered proteins are already less stable than the globular protein and exist as interconverting conformational ensembles. Therefore one might expect that these proteins will follow different rules. Here, a certain mutation may not abolish all conformations but simply a subset of the conformational ensemble. On shorter time scales, mutations that affect the equilibrium of the conformational ensemble can be regarded as influencing the function rather than the structure, while on longer time scales large changes in the conformational ensemble from a pair of gene duplicates may no longer overlap and can be regarded as changing the structure or fold. This would reflect a fold transition; a change from one fold or conformational ensemble into a distinctly different fold or conformational ensemble. Hence, structurally disordered proteins (proteins present as conformational ensembles) provide a mechanism for neostructuralization. An example of this concept is illustrated in Figure 2.


The evolution of protein structures and structural ensembles under functional constraint.

Siltberg-Liberles J, Grahnen JA, Liberles DA - Genes (Basel) (2011)

Evolution of an energy landscape and its conformational ensemble after gene duplication. At the root, the gene giving rise to the protein with the blue energy landscape resulting in conformations A to G is duplicated. At the next speciation event we can see that the two different gene copies have evolved along different trajectories. The blue copy at the speciation node has evolved under negative selection and resembles the ancient blue. The green copy at the speciation node has evolved under positive selection and of the original conformational ensemble, conformations F and G are no longer forming, but a new conformation, H, is forming. In addition, the equilibrium of the conformations is different in the blue vs. green energy landscapes. From the speciation node down to the extant sequences, blue is much conserved, while green although under negative selection, will lose conformation D, in one lineage. Analysis of the extant sequences would show that blue and green are structurally disordered homologs. However, although all these proteins are structurally disordered, the conformational ensembles differ between blue and green (while being the same within the blue copies, and very similar within the green copies.)
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927589&req=5

f2-genes-02-00748: Evolution of an energy landscape and its conformational ensemble after gene duplication. At the root, the gene giving rise to the protein with the blue energy landscape resulting in conformations A to G is duplicated. At the next speciation event we can see that the two different gene copies have evolved along different trajectories. The blue copy at the speciation node has evolved under negative selection and resembles the ancient blue. The green copy at the speciation node has evolved under positive selection and of the original conformational ensemble, conformations F and G are no longer forming, but a new conformation, H, is forming. In addition, the equilibrium of the conformations is different in the blue vs. green energy landscapes. From the speciation node down to the extant sequences, blue is much conserved, while green although under negative selection, will lose conformation D, in one lineage. Analysis of the extant sequences would show that blue and green are structurally disordered homologs. However, although all these proteins are structurally disordered, the conformational ensembles differ between blue and green (while being the same within the blue copies, and very similar within the green copies.)
Mentions: One of the mechanisms for generating novel or partitioned functions is through gene duplications/gene redundancy. It was recently shown that gene retention after gene duplication is higher for genes with many phosphorylation sites [71]. Structurally disordered proteins are enriched in phosphorylation sites and perhaps the thermodynamics of disorder in itself can provide an explanation. For globular structured proteins one main determinant for fixing a mutation is the effect of the mutation on the stability of the protein fold. Structurally disordered proteins are already less stable than the globular protein and exist as interconverting conformational ensembles. Therefore one might expect that these proteins will follow different rules. Here, a certain mutation may not abolish all conformations but simply a subset of the conformational ensemble. On shorter time scales, mutations that affect the equilibrium of the conformational ensemble can be regarded as influencing the function rather than the structure, while on longer time scales large changes in the conformational ensemble from a pair of gene duplicates may no longer overlap and can be regarded as changing the structure or fold. This would reflect a fold transition; a change from one fold or conformational ensemble into a distinctly different fold or conformational ensemble. Hence, structurally disordered proteins (proteins present as conformational ensembles) provide a mechanism for neostructuralization. An example of this concept is illustrated in Figure 2.

Bottom Line: This ties back to a question of the role of neostructuralization and how it relates to selection on sequences for functions.The relationship between metastability, the fitness landscape, sequence divergence, and organismal effective population size is explored.Lastly, a brief discussion of modeling the evolution of sequences of ordered and disordered proteins is entertained.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, University of Wyoming, Laramie, WY 82071, USA. jliberle@uwyo.edu.

ABSTRACT
Protein sequence, structure, and function are inherently linked through evolution and population genetics. Our knowledge of protein structure comes from solved structures in the Protein Data Bank (PDB), our knowledge of sequence through sequences found in the NCBI sequence databases (http://www.ncbi.nlm.nih.gov/), and our knowledge of function through a limited set of in-vitro biochemical studies. How these intersect through evolution is described in the first part of the review. In the second part, our understanding of a series of questions is addressed. This includes how sequences evolve within structures, how evolutionary processes enable structural transitions, how the folding process can change through evolution and what the fitness impacts of this might be. Moving beyond static structures, the evolution of protein kinetics (including normal modes) is discussed, as is the evolution of conformational ensembles and structurally disordered proteins. This ties back to a question of the role of neostructuralization and how it relates to selection on sequences for functions. The relationship between metastability, the fitness landscape, sequence divergence, and organismal effective population size is explored. Lastly, a brief discussion of modeling the evolution of sequences of ordered and disordered proteins is entertained.

No MeSH data available.