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Adaptive threonine increase in transmembrane regions of mitochondrial proteins in higher primates.

Kitazoe Y, Kishino H, Hasegawa M, Nakajima N, Thorne JL, Tanaka M - PLoS ONE (2008)

Bottom Line: This Thr increase involved the replacement of hydrophobic AAs in the membrane interior.Because crucial roles of Thr and Ser in membrane proteins have been proposed to be the formation of hydrogen bonds enhancing helix-helix interactions, the Thr increase detected in the higher primates might be adaptive by serving to reinforce stability of mt proteins in the inner membrane.The correlation between Thr composition in the membrane interior and the longevity of animals is striking, especially because some mt functions are thought to be involved in aging.

View Article: PubMed Central - PubMed

Affiliation: Center of Medical Information Science, Kochi Medical School, Nankoku, Kochi, Japan. kitazoey@kochi-u.ac.jp

ABSTRACT

Background: The mitochondrial (mt) gene tree of placental mammals reveals a very strong acceleration of the amino acid (AA) replacement rate and a change in AA compositional bias in the lineage leading to the higher primates (simians), in contrast to the nuclear gene tree. Whether this acceleration and compositional bias were caused by adaptive evolution at the AA level or directional mutation pressure at the DNA level has been vigorously debated.

Methodology/principal findings: Our phylogenetic analysis indicates that the rate acceleration in the simian lineage is accompanied by a marked increase in threonine (Thr) residues in the transmembrane helix regions of mt DNA-encoded proteins. This Thr increase involved the replacement of hydrophobic AAs in the membrane interior. Even after accounting for lack of independence due to phylogeny, a regression analysis reveals a statistical significant positive correlation between Thr composition and longevity in primates.

Conclusion/significance: Because crucial roles of Thr and Ser in membrane proteins have been proposed to be the formation of hydrogen bonds enhancing helix-helix interactions, the Thr increase detected in the higher primates might be adaptive by serving to reinforce stability of mt proteins in the inner membrane. The correlation between Thr composition in the membrane interior and the longevity of animals is striking, especially because some mt functions are thought to be involved in aging.

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Related in: MedlinePlus

Thr distribution measured from the membrane surface on the matrix side.Figure estimates the spatial distribution of Thr residues in the 12 mt proteins. The x-values stand for the AA site numbers measured from the inner membrane surface on the matrix side. The inner and outer surface positions (vertical lines) of the helices in each protein AA sequence were inferred from a secondary structure analysis of the mt proteins [21]–[23]. The black and red circles show the Thr compositional distribution (%) in the root sequence (the most recent common ancestor of the tree shrew and primates) of the primates and that (the averaged value) in the simian terminal sequences, respectively. The blue circles represent the increased fraction (gain) of Thr residues in the simians.
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pone-0003343-g004: Thr distribution measured from the membrane surface on the matrix side.Figure estimates the spatial distribution of Thr residues in the 12 mt proteins. The x-values stand for the AA site numbers measured from the inner membrane surface on the matrix side. The inner and outer surface positions (vertical lines) of the helices in each protein AA sequence were inferred from a secondary structure analysis of the mt proteins [21]–[23]. The black and red circles show the Thr compositional distribution (%) in the root sequence (the most recent common ancestor of the tree shrew and primates) of the primates and that (the averaged value) in the simian terminal sequences, respectively. The blue circles represent the increased fraction (gain) of Thr residues in the simians.

Mentions: As described in Materials and Methods, we analyzed in more detail the Hoa→Thr flow in the three lineages of simians and also sperm whale and elephant, by locally estimating the node sequences of the three lineages at the DNA level. The analysis displayed both substantial increases in Thr/Leu residues and reductions in Ile/Met residues (Figure 3A). The increase in hydrophobic Leu residues accompanied a compensatory decline in other hydrophobic residues. Consequently, only the Hoa→Thr flow appeared. We next performed a protein structure analysis [21]–[23], by introducing a moving average, S, of local hydrophobic scores around each AA site (Materials and Methods), and expressed the local hydrophobic environment of the root sequences using an AA scale model (Table S1 gives the hydrophobic score of each AA with an orthodox model [24]). We find that the Hoa→Thr flow occurred especially in the hydrophobic region (S>0.6) of mt proteins (the frequency distribution of S-values gives the maximum at S = 0.6, whereas the remaining 11 AAs (Rma) except for Hoa and Thr had no flow (Figure 3B and Table 1A). This hydrophobicity dependence of the Hoa→Thr flow was also observed in the sperm whale and elephant lineages (Table 1B and 1C). To investigate this dependence in detail, we estimated the spatial distribution of the Thr residues around the membrane interior using a transmembrane analysis to predict the helical regions of the AA sequences [22], [23]. Here, the distribution was estimated in the simian and root sequences. It was measured from the AA coordinates of the membrane surface on the matrix side by splitting an AA sequence into fragments, each of which was embedded only once in the membrane interior. Figure 4 demonstrates that the Thr increase in the lineage leading to the simians took place preferentially in the membrane-spanning (helix) regions. Because the maximum parsimony reconstruction of the root sequence may be biased toward the consensus state [25] and this could produce an artifact that incorrectly suggests an AA composition flow, we conducted an additional analysis with the simian lineage. We defined the root of the simians as the most recent common ancestor of the tree shrew and the primates. Then, the root sequence estimated could be approximately substituted by the real sequence of the tree shrew, because the branch length between the root and the tree shrew is very short, as seen in Figure 1. This substitution was useful to confirm that the estimated root sequence is not biased, and provided a similar result of the Hoa→Thr flow to that given by the estimated root sequence (Tables 1A versus 1D). Table S2 lists the AA positions of mt proteins at which the Hoa sites of the primate root sequence in the hydrophobic region (S>0.6) changed to Thr in chimpanzee or human.


Adaptive threonine increase in transmembrane regions of mitochondrial proteins in higher primates.

Kitazoe Y, Kishino H, Hasegawa M, Nakajima N, Thorne JL, Tanaka M - PLoS ONE (2008)

Thr distribution measured from the membrane surface on the matrix side.Figure estimates the spatial distribution of Thr residues in the 12 mt proteins. The x-values stand for the AA site numbers measured from the inner membrane surface on the matrix side. The inner and outer surface positions (vertical lines) of the helices in each protein AA sequence were inferred from a secondary structure analysis of the mt proteins [21]–[23]. The black and red circles show the Thr compositional distribution (%) in the root sequence (the most recent common ancestor of the tree shrew and primates) of the primates and that (the averaged value) in the simian terminal sequences, respectively. The blue circles represent the increased fraction (gain) of Thr residues in the simians.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2553178&req=5

pone-0003343-g004: Thr distribution measured from the membrane surface on the matrix side.Figure estimates the spatial distribution of Thr residues in the 12 mt proteins. The x-values stand for the AA site numbers measured from the inner membrane surface on the matrix side. The inner and outer surface positions (vertical lines) of the helices in each protein AA sequence were inferred from a secondary structure analysis of the mt proteins [21]–[23]. The black and red circles show the Thr compositional distribution (%) in the root sequence (the most recent common ancestor of the tree shrew and primates) of the primates and that (the averaged value) in the simian terminal sequences, respectively. The blue circles represent the increased fraction (gain) of Thr residues in the simians.
Mentions: As described in Materials and Methods, we analyzed in more detail the Hoa→Thr flow in the three lineages of simians and also sperm whale and elephant, by locally estimating the node sequences of the three lineages at the DNA level. The analysis displayed both substantial increases in Thr/Leu residues and reductions in Ile/Met residues (Figure 3A). The increase in hydrophobic Leu residues accompanied a compensatory decline in other hydrophobic residues. Consequently, only the Hoa→Thr flow appeared. We next performed a protein structure analysis [21]–[23], by introducing a moving average, S, of local hydrophobic scores around each AA site (Materials and Methods), and expressed the local hydrophobic environment of the root sequences using an AA scale model (Table S1 gives the hydrophobic score of each AA with an orthodox model [24]). We find that the Hoa→Thr flow occurred especially in the hydrophobic region (S>0.6) of mt proteins (the frequency distribution of S-values gives the maximum at S = 0.6, whereas the remaining 11 AAs (Rma) except for Hoa and Thr had no flow (Figure 3B and Table 1A). This hydrophobicity dependence of the Hoa→Thr flow was also observed in the sperm whale and elephant lineages (Table 1B and 1C). To investigate this dependence in detail, we estimated the spatial distribution of the Thr residues around the membrane interior using a transmembrane analysis to predict the helical regions of the AA sequences [22], [23]. Here, the distribution was estimated in the simian and root sequences. It was measured from the AA coordinates of the membrane surface on the matrix side by splitting an AA sequence into fragments, each of which was embedded only once in the membrane interior. Figure 4 demonstrates that the Thr increase in the lineage leading to the simians took place preferentially in the membrane-spanning (helix) regions. Because the maximum parsimony reconstruction of the root sequence may be biased toward the consensus state [25] and this could produce an artifact that incorrectly suggests an AA composition flow, we conducted an additional analysis with the simian lineage. We defined the root of the simians as the most recent common ancestor of the tree shrew and the primates. Then, the root sequence estimated could be approximately substituted by the real sequence of the tree shrew, because the branch length between the root and the tree shrew is very short, as seen in Figure 1. This substitution was useful to confirm that the estimated root sequence is not biased, and provided a similar result of the Hoa→Thr flow to that given by the estimated root sequence (Tables 1A versus 1D). Table S2 lists the AA positions of mt proteins at which the Hoa sites of the primate root sequence in the hydrophobic region (S>0.6) changed to Thr in chimpanzee or human.

Bottom Line: This Thr increase involved the replacement of hydrophobic AAs in the membrane interior.Because crucial roles of Thr and Ser in membrane proteins have been proposed to be the formation of hydrogen bonds enhancing helix-helix interactions, the Thr increase detected in the higher primates might be adaptive by serving to reinforce stability of mt proteins in the inner membrane.The correlation between Thr composition in the membrane interior and the longevity of animals is striking, especially because some mt functions are thought to be involved in aging.

View Article: PubMed Central - PubMed

Affiliation: Center of Medical Information Science, Kochi Medical School, Nankoku, Kochi, Japan. kitazoey@kochi-u.ac.jp

ABSTRACT

Background: The mitochondrial (mt) gene tree of placental mammals reveals a very strong acceleration of the amino acid (AA) replacement rate and a change in AA compositional bias in the lineage leading to the higher primates (simians), in contrast to the nuclear gene tree. Whether this acceleration and compositional bias were caused by adaptive evolution at the AA level or directional mutation pressure at the DNA level has been vigorously debated.

Methodology/principal findings: Our phylogenetic analysis indicates that the rate acceleration in the simian lineage is accompanied by a marked increase in threonine (Thr) residues in the transmembrane helix regions of mt DNA-encoded proteins. This Thr increase involved the replacement of hydrophobic AAs in the membrane interior. Even after accounting for lack of independence due to phylogeny, a regression analysis reveals a statistical significant positive correlation between Thr composition and longevity in primates.

Conclusion/significance: Because crucial roles of Thr and Ser in membrane proteins have been proposed to be the formation of hydrogen bonds enhancing helix-helix interactions, the Thr increase detected in the higher primates might be adaptive by serving to reinforce stability of mt proteins in the inner membrane. The correlation between Thr composition in the membrane interior and the longevity of animals is striking, especially because some mt functions are thought to be involved in aging.

Show MeSH
Related in: MedlinePlus