Ss can occur if the sequence diverges beyond recognition or if

Ss can occur if the sequence diverges beyond recognition or if the region is physically lost [21]. A domain (and a linker) can also appear lost, if different isoforms or partial sequences are considered. Over time, the domain composition of the p53 Oroxylin AMedChemExpress Baicalein 6-methyl ether family has been altered, with high rate of domain loss in Ecdysozoa where many p53 DBD containing proteins are too short to contain the other domains, but some also have highly divergent OD and SAM domains that no longer generate a significant Pfam domain prediction. In early vertebrates, an ancestral four domain cassette protein was duplicated and subdivided into different proteins, p53, p63, and p73. The p53 clade lost SAM and experienced rapid change in the TAD signature sequence. The p63/p73 clade appears to not change in its current domain organization, but the sequence that once encoded the TAD domain (and may still be present in p63 and p73) has faded beyond recognition, probably prior to the duplication that yielded p63 and p73. Thus, it is possible that a subfunctionalization event followed the first duplication; p53 got most of the TAD domain function, while the p63/p73 ancestor kept the SAM domain.Sequence divergence: Rate changes at homologous sitesFollowing the gene duplication resulting in p63 and p73, p63 is much more constrained, manifested by highly conserved sequences among different species, while the p73 clade is less conserved in sequence. The phylogenies based on full-length protein sequence alignments and their corresponding nucleotide sequence alignment reveal that the rate of sequence divergence is greater in the p53 clade (S2 Fig). A pairwise comparison (based on the full-length protein alignment) between human and shark sequences in the p53, p63, and p73 clades respectively reveal 51.55 , 76.13 and 76.65 sequence identity. Consequently, p63 and p73 are more similar, with 61.81 sequence identity when comparing shark sequences and 59.24 sequence identity when comparing the human sequences. Further, pairwise sequence identity for shark p53 vs. shark p63 and shark p73, reveal 49.02 and 49.86 respectively. Interestingly, the same comparisons made with the human proteins, p53 vs. p63 and p73, reveal 40.99 and 42.82 pairwise sequence identity, respectively. In summary, the shark p53 family proteins have diverged less than the human counterparts, in accordance with the significantly slower divergence rate found in sharks compared to other vertebrates [22].Evolutionary dynamics of structural disorderHighly dependent fpsyg.2017.00209 on conformational VER-52296 web flexibility, the proteins in the p53 family are known to vary in stability; p63 is more stable than p73 and the least stable is p53 [23]. Limited studies of p53 proteins from different species show variation in levels of stability also within the pPLOS ONE | DOI:10.1371/journal.pone.0151961 March 22,5 /Evolutionary Dynamics of Sequence, Structure, and Phosphorylation in the p53, p63, and p73 Paralogsclade. Here, we predicted structural disorder propensity as an approximation for conformational flexibility. The disorder profile for the entire p53 family reveals that the predicted disorder propensity per site is highly variable across the entire SART.S23503 length of the protein (Fig 2). Dividing the p53 family into the p53, p63, and p73 clades, reveals that the p63 protein is conserved in disorder propensity across the entire protein, while p53 and p73 show multiple regions with varying disorder propensities across their clades (Fig 2). Classifying t.Ss can occur if the sequence diverges beyond recognition or if the region is physically lost [21]. A domain (and a linker) can also appear lost, if different isoforms or partial sequences are considered. Over time, the domain composition of the p53 family has been altered, with high rate of domain loss in Ecdysozoa where many p53 DBD containing proteins are too short to contain the other domains, but some also have highly divergent OD and SAM domains that no longer generate a significant Pfam domain prediction. In early vertebrates, an ancestral four domain cassette protein was duplicated and subdivided into different proteins, p53, p63, and p73. The p53 clade lost SAM and experienced rapid change in the TAD signature sequence. The p63/p73 clade appears to not change in its current domain organization, but the sequence that once encoded the TAD domain (and may still be present in p63 and p73) has faded beyond recognition, probably prior to the duplication that yielded p63 and p73. Thus, it is possible that a subfunctionalization event followed the first duplication; p53 got most of the TAD domain function, while the p63/p73 ancestor kept the SAM domain.Sequence divergence: Rate changes at homologous sitesFollowing the gene duplication resulting in p63 and p73, p63 is much more constrained, manifested by highly conserved sequences among different species, while the p73 clade is less conserved in sequence. The phylogenies based on full-length protein sequence alignments and their corresponding nucleotide sequence alignment reveal that the rate of sequence divergence is greater in the p53 clade (S2 Fig). A pairwise comparison (based on the full-length protein alignment) between human and shark sequences in the p53, p63, and p73 clades respectively reveal 51.55 , 76.13 and 76.65 sequence identity. Consequently, p63 and p73 are more similar, with 61.81 sequence identity when comparing shark sequences and 59.24 sequence identity when comparing the human sequences. Further, pairwise sequence identity for shark p53 vs. shark p63 and shark p73, reveal 49.02 and 49.86 respectively. Interestingly, the same comparisons made with the human proteins, p53 vs. p63 and p73, reveal 40.99 and 42.82 pairwise sequence identity, respectively. In summary, the shark p53 family proteins have diverged less than the human counterparts, in accordance with the significantly slower divergence rate found in sharks compared to other vertebrates [22].Evolutionary dynamics of structural disorderHighly dependent fpsyg.2017.00209 on conformational flexibility, the proteins in the p53 family are known to vary in stability; p63 is more stable than p73 and the least stable is p53 [23]. Limited studies of p53 proteins from different species show variation in levels of stability also within the pPLOS ONE | DOI:10.1371/journal.pone.0151961 March 22,5 /Evolutionary Dynamics of Sequence, Structure, and Phosphorylation in the p53, p63, and p73 Paralogsclade. Here, we predicted structural disorder propensity as an approximation for conformational flexibility. The disorder profile for the entire p53 family reveals that the predicted disorder propensity per site is highly variable across the entire SART.S23503 length of the protein (Fig 2). Dividing the p53 family into the p53, p63, and p73 clades, reveals that the p63 protein is conserved in disorder propensity across the entire protein, while p53 and p73 show multiple regions with varying disorder propensities across their clades (Fig 2). Classifying t.