Ancient and Recent Adaptive Evolution of Primate Non-Homologous End Joining Genes
Figure 4
XRCC4, a component of the NHEJ ligase complex, shows a clustered signature of positive selection.
A) A co-crystal of the human XRCC4 homodimer (grey) in complex with a fragment of its binding partner Lig4 (blue) has been solved (PDB 1IK9)[38]. The ligase-binding domain of XRCC4 is shown in yellow. The C-terminal domain of the 336 amino acid protein is unstructured and had to be truncated for crystallization. This portion has been artificially indicated by the wavy black line. In the crystal structure, the two monomeric chains are different lengths. Chain A (dark gray) is comprised of residues 1–211, while chain B (light gray) is comprised of residues 1–201. Two of the amino acids positions found to be under positive selection (205 and 211; red globes) could be mapped only to the longer of the two monomers (chain A). Sites 216, 218, 243, and 292 could not be mapped to either monomer. Their approximate location is marked with a pink asterisks on the linear schematic of the C-terminal domain. B) A linear domain diagram of XRCC4 is shown, with the approximate location of the amino acid sites under positive selection marked with asterisks. An amino acid alignment in this region for the 20 primate species used in this study is shown, with residues found to be under positive selection highlighted in gray. Residue 211, which was identified as being subject to positive selection, lies at the third position within the SUMOylation consensus site (IKQE; denoted in red), with the neighboring lysine being SUMOylated[41]. Another amino acid position that has evolved under positive selection, residue 243, is located just four positions upstream of a A247S human disease mutation which has been linked to oral cancer susceptibility[43], and three positions downstream of the human Q240P polymorphism (these two sites are underlined in the human amino acid sequence). Secondary structure predictions and confidence values (0, low; 9,high) were obtained with the PSIPRED server[93]. “H” and the barrel shape denote the very end of the long alpha helix that is observed in the crystal structure. Downstream of this, “C” indicates the unstructured region.