Limits...
Structural and functional implications of positive selection at the primate angiogenin gene.

Osorio DS, Antunes A, Ramos MJ - BMC Evol. Biol. (2007)

Bottom Line: Moreover, 11 sites were exposed to the surface of the protein indicating that they may influence the interactions performed by ANG.These sites mapped onto the main functional regions of the ANG protein.However, other possibilities to be considered arise from the possible involvement of ANG in innate immunity and the potential influence or co-evolution with its interacting proteins and ligands.

View Article: PubMed Central - HTML - PubMed

Affiliation: REQUIMTE, Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal. daniel.s.osorio@gmail.com

ABSTRACT

Background: Angiogenesis, the formation of new blood vessels, is a primordial process in development and its dysregulation has a central role in the pathogenesis of many diseases. Angiogenin (ANG), a peculiar member of the RNase A superfamily, is a potent inducer of angiogenesis involved in many different types of cancer, amyotrophic lateral sclerosis and also with a possible role in the innate immune defense. The evolutionary path of this family has been a highly dynamic one, where positive selection has played a strong role. In this work we used a combined gene and protein level approach to determine the main sites under diversifying selection on the primate ANG gene and analyze its structural and functional implications.

Results: We obtained evidence for positive selection in the primate ANG gene. Site specific analysis pointed out 15 sites under positive selection, most of which also exhibited drastic changes in amino acid properties. The mapping of these sites in the ANG 3D-structure described five clusters, four of which were located in functional regions: two in the active site region, one in the nucleolar location signal and one in the cell-binding site. Eight of the 15 sites under selection in the primate ANG gene were highly or moderately conserved in the RNase A family, suggesting a directed event and not a simple consequence of local structural or functional permissiveness. Moreover, 11 sites were exposed to the surface of the protein indicating that they may influence the interactions performed by ANG.

Conclusion: Using a maximum likelihood gene level analysis we identified 15 sites under positive selection in the primate ANG genes, that were further corroborated through a protein level analysis of radical changes in amino acid properties. These sites mapped onto the main functional regions of the ANG protein. The fact that evidence for positive selection is present in all ANG regions required for angiogenesis may be a good indication that angiogenesis is the process under selection. However, other possibilities to be considered arise from the possible involvement of ANG in innate immunity and the potential influence or co-evolution with its interacting proteins and ligands.

Show MeSH

Related in: MedlinePlus

ConSurf conservation scores for sites under positive selection. Comparison of ConSurf conservation scores for primate angiogenin protein sequences and a pool of 168 non-angiogenin RNase sequences. (*) Indicates sites that were below the confidence cut-off for this analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2194721&req=5

Figure 2: ConSurf conservation scores for sites under positive selection. Comparison of ConSurf conservation scores for primate angiogenin protein sequences and a pool of 168 non-angiogenin RNase sequences. (*) Indicates sites that were below the confidence cut-off for this analysis.

Mentions: In order to assess if the sites under selection were only variant in angiogenin or throughout the whole RNase A superfamily, the primate ANG sequences were compared with a pool of 168 non-angiogenin RNase sequences using the ConSurf web server [38]. This software calculates evolutionary conservation scores (1 to 9) based on alignments and a reference structure (human ANG 3D-structure) (figure 2). The sites under positive selection in the primate sequences presented low conservation scores of 1, except for site 52 that had a score of 3. Conservation scores for sites 32, 34 and 52 were below the confidence cut-off for ConSurf. When analyzed in the pool of RNase sequences, sites 11, 84 and 103 presented a high conservation score of 7; whereas sites 4, 8, 51 and 34, 93 had moderate conservation scores of 5 and 4, respectively. The remaining sites had lower scores. It is striking that eight of the 15 sites detected under selection in the primate ANG gene, including three of the five type I sites, are highly or moderately conserved in the RNase A family. Although this might result in part from the structural and functional divergence between the members of this family, it also indicates that these sites are not subject to random variation throughout the family as a result of structural and functional permissiveness on their locations.


Structural and functional implications of positive selection at the primate angiogenin gene.

Osorio DS, Antunes A, Ramos MJ - BMC Evol. Biol. (2007)

ConSurf conservation scores for sites under positive selection. Comparison of ConSurf conservation scores for primate angiogenin protein sequences and a pool of 168 non-angiogenin RNase sequences. (*) Indicates sites that were below the confidence cut-off for this analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2194721&req=5

Figure 2: ConSurf conservation scores for sites under positive selection. Comparison of ConSurf conservation scores for primate angiogenin protein sequences and a pool of 168 non-angiogenin RNase sequences. (*) Indicates sites that were below the confidence cut-off for this analysis.
Mentions: In order to assess if the sites under selection were only variant in angiogenin or throughout the whole RNase A superfamily, the primate ANG sequences were compared with a pool of 168 non-angiogenin RNase sequences using the ConSurf web server [38]. This software calculates evolutionary conservation scores (1 to 9) based on alignments and a reference structure (human ANG 3D-structure) (figure 2). The sites under positive selection in the primate sequences presented low conservation scores of 1, except for site 52 that had a score of 3. Conservation scores for sites 32, 34 and 52 were below the confidence cut-off for ConSurf. When analyzed in the pool of RNase sequences, sites 11, 84 and 103 presented a high conservation score of 7; whereas sites 4, 8, 51 and 34, 93 had moderate conservation scores of 5 and 4, respectively. The remaining sites had lower scores. It is striking that eight of the 15 sites detected under selection in the primate ANG gene, including three of the five type I sites, are highly or moderately conserved in the RNase A family. Although this might result in part from the structural and functional divergence between the members of this family, it also indicates that these sites are not subject to random variation throughout the family as a result of structural and functional permissiveness on their locations.

Bottom Line: Moreover, 11 sites were exposed to the surface of the protein indicating that they may influence the interactions performed by ANG.These sites mapped onto the main functional regions of the ANG protein.However, other possibilities to be considered arise from the possible involvement of ANG in innate immunity and the potential influence or co-evolution with its interacting proteins and ligands.

View Article: PubMed Central - HTML - PubMed

Affiliation: REQUIMTE, Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal. daniel.s.osorio@gmail.com

ABSTRACT

Background: Angiogenesis, the formation of new blood vessels, is a primordial process in development and its dysregulation has a central role in the pathogenesis of many diseases. Angiogenin (ANG), a peculiar member of the RNase A superfamily, is a potent inducer of angiogenesis involved in many different types of cancer, amyotrophic lateral sclerosis and also with a possible role in the innate immune defense. The evolutionary path of this family has been a highly dynamic one, where positive selection has played a strong role. In this work we used a combined gene and protein level approach to determine the main sites under diversifying selection on the primate ANG gene and analyze its structural and functional implications.

Results: We obtained evidence for positive selection in the primate ANG gene. Site specific analysis pointed out 15 sites under positive selection, most of which also exhibited drastic changes in amino acid properties. The mapping of these sites in the ANG 3D-structure described five clusters, four of which were located in functional regions: two in the active site region, one in the nucleolar location signal and one in the cell-binding site. Eight of the 15 sites under selection in the primate ANG gene were highly or moderately conserved in the RNase A family, suggesting a directed event and not a simple consequence of local structural or functional permissiveness. Moreover, 11 sites were exposed to the surface of the protein indicating that they may influence the interactions performed by ANG.

Conclusion: Using a maximum likelihood gene level analysis we identified 15 sites under positive selection in the primate ANG genes, that were further corroborated through a protein level analysis of radical changes in amino acid properties. These sites mapped onto the main functional regions of the ANG protein. The fact that evidence for positive selection is present in all ANG regions required for angiogenesis may be a good indication that angiogenesis is the process under selection. However, other possibilities to be considered arise from the possible involvement of ANG in innate immunity and the potential influence or co-evolution with its interacting proteins and ligands.

Show MeSH
Related in: MedlinePlus