期刊
SCIENTIFIC REPORTS
卷 11, 期 1, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s41598-021-88400-7
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资金
- National Institutes of Health (NIH)
- Division of Intramural Research of the National Institute of Environmental Health Sciences, National Institutes of Health [ZIA-ES050111, Z01-ES043010]
- KRIBB Korean Biomedical Scientist Fellowship Program, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Republic of Korea
The study investigated the phosphopeptide binding characteristics of Nbs1 BRCT1/2 and identified structural homology with TopBP1 BRCT7/8 through molecular modeling. These features provide insight into the basis for interaction of SDT motifs with the BRCT1/2 domains and allowed identification of high and low affinity ligands.
Human Nbs1, a component of the MRN complex involved in DNA double strand break repair, contains a concatenated N-terminal FHA-BRCT1/2 sequence that supports interaction with multiple phosphopeptide binding partners. MDC1 binding localizes Nbs1 to the damage site, while binding of CDK-phosphorylated CtIP activates additional ATM-dependent CtIP phosphorylation, modulating substrate-dependent resection. We have investigated the phosphopeptide binding characteristics of Nbs1 BRCT1/2 based on a molecular modeling approach that revealed structural homology with the tandem TopBP1 BRCT7/8 domains. Relevance of the model was substantiated by the ability of TopBP1-binding FANCJ phosphopeptide to interact with hsNbsBRCT1/2, albeit with lower affinity. The modeled BRCT1/2 is characterized by low pSer/pThr selectivity, preference for a cationic residue at the+2 position, and an inter-domain binding cleft selective for hydrophobic residues at the+3/+4 positions. These features provide insight into the basis for interaction of SDT motifs with the BRCT1/2 domains and allowed identification of CtIP pSer347- and pThr847-containing phosphopeptides as high and lower affinity ligands, respectively. Among other binding partners considered, rodent XRCC1 contains an SDT sequence in the second linker consistent with high-affinity Nbs1 binding, while human XRCC1 lacks this motif, but contains other phosphorylated sequences that exhibit low-affinity binding.
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