6tyu | pdb_00006tyu
Structure of Ku80 von Willebrand domain complexed with MRI Ku Binding Motif
Structural highlights
FunctionCYREN_HUMAN Cell-cycle-specific regulator of classical non-homologous end joining (NHEJ) of DNA double-strand break (DSB) repair, which can act both as an activator or inhibitor of NHEJ, depending on the cell cycle phase (PubMed:24610814, PubMed:28959974). Acts as a regulator of DNA repair pathway choice by specifically inhibiting classical NHEJ during the S and G2 phases, thereby promoting error-free repair by homologous recombination during cell cycle phases when sister chromatids are present (PubMed:28959974). Preferentially protects single-stranded overhangs at break sites by inhibiting classical NHEJ, thereby creating a local environment that favors homologous recombination (PubMed:28959974). Acts via interaction with XRCC5/Ku80 and XRCC6/Ku70 (PubMed:28959974). In contrast, acts as an activator of NHEJ during G1 phase of the cell cycle: promotes classical NHEJ in G1 phase cells via multivalent interactions that increase the affinity of DNA damage response proteins for DSB-associated chromatin. Also involved in immunoglobulin V(D)J recombination (By similarity). May also act as an indirect regulator of proteasome (By similarity).[UniProtKB:Q09HN1][UniProtKB:Q8BHZ5][1] [2] Publication Abstract from PubMedThe N-terminal von Willebrand domain of Ku80 supports interactions with a Ku binding motif (KBM) that has been identified in at least three other DNA repair proteins: the non-homologous end joining (NHEJ) scaffold APLF, the modulator of retrovirus infection, MRI, and the Werner syndrome protein (WRN). A second, more recently identified Ku binding motif present in XLF and several other proteins (KBMX) has also been reported to interact with this domain. The isolated Ku80 von Willebrand antigen domain (vWA) from Xenopus laevis has a sequence that is 60% identical with the human domain, is readily expressed and has been used to investigate these interactions. Structural characterization of the complexes formed with the KBM motifs in human APLF, MRI, and WRN identify a conserved binding site that is consistent with previously-reported mutational studies. In contrast with the KBM binding site, structural studies indicate that the KBMX site is occluded by a distorted helix. Fluorescence polarization and (19)F NMR studies of a fluorinated XLF C-terminal peptide failed to indicate any interaction with the frog vWA. It was hypothesized that availability of this binding site is conditional, i.e., dependent on specific experimental conditions or other repair factors to make the site available for binding. Modulating the fraction of KBMX-accessible binding site mutationally demonstrated that the more open site is capable of binding the KBMX(XLF) motif peptide. It is suggested that the conditional nature of KBMX binding limits formation of non-productive complexes so that activation-dependent site availability can more optimally support advancing the synapsis process. Ligand binding characteristics of the Ku80 von Willebrand domain.,Kim K, Min J, Kirby TW, Gabel SA, Pedersen LC, London RE DNA Repair (Amst). 2019 Oct 24;85:102739. doi: 10.1016/j.dnarep.2019.102739. PMID:31733588[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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