title: Structural basis of DNA ligase IV-Artemis interaction in nonhomologous end-joining.
abstract: DNA ligase IV (LigIV) and Artemis are central components of the nonhomologous end-joining (NHEJ) machinery that is required for V(D)J recombination and the maintenance of genomic integrity in mammalian cells. We report here crystal structures of the LigIV DNA binding domain (DBD) in both its apo form and in complex with a peptide derived from the Artemis C-terminal region. We show that LigIV interacts with Artemis through an extended hydrophobic surface. In particular, we find that the helix α2 in LigIV-DBD is longer than in other mammalian ligases and presents residues that specifically interact with the Artemis peptide, which adopts a partially helical conformation on binding. Mutations of key residues on the LigIV-DBD hydrophobic surface abolish the interaction. Together, our results provide structural insights into the specificity of the LigIV-Artemis interaction and how the enzymatic activities of the two proteins may be coordinated during NHEJ.
authors.affiliation: Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: De Ioannes
authors.forename: Shruti
authors.initials: S
authors.lastname: Malu
authors.forename: Patricia
authors.initials: P
authors.lastname: Cortes
authors.forename: Aneel K
authors.initials: AK
authors.lastname: Aggarwal
mesh_terms: D018360:Crystallography, X-Ray; D059766:DNA End-Joining Repair / Q000502:physiology*; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004720:Endonucleases; D042822:Genomic Instability; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D004268:DNA-Binding Proteins; C000607893:LIG4 protein, human; D009687:Nuclear Proteins; C426344:DCLRE1C protein, human; D004720:Endonucleases; D011088:DNA Ligases; D000072481:DNA Ligase ATP