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C1188D mutation abolishes specific recognition between MLL1-CXXC domain and CpG site by inducing conformational switch of flexible N-terminal |
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| Authors: | Jiawen Chen Yanping Qi Yong Duan Mojie Duan Minghui Yang |
| Institution: | 1. Key Laboratory of Magnetic Resonance in Biological Systems, National Center for Magnetic Resonances in Wuhan, State Key laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan, China;2. Key Laboratory of Magnetic Resonance in Biological Systems, National Center for Magnetic Resonances in Wuhan, State Key laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan, China
College of Physical Science and Technology, Central China Normal University, Wuhan, China;3. Department of Biomedical Engineering and UC Davis Genome Center, University of California at Davis, Davis, California, USA;4. Key Laboratory of Magnetic Resonance in Biological Systems, National Center for Magnetic Resonances in Wuhan, State Key laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan, China Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan, China |
| Abstract: | Mixed lineage leukemia protein (MLL1 protein) recognizes the CpG site via its CXXC domain and is frequently associated with leukemia. The specific recognition is abolished by C1188D mutation, which also prevents MLL-related leukemia. In this paper, multiple molecular dynamic (MD) simulations were performed to investigate the mechanism of recognition and influences of C1188D mutation. Started from fully dissociated DNA and MLL1-CXXC domain, remarkably, the center of mass (COM) of MLL1-CXXC domain quickly concentrates on the vicinity of the CpG site in all 53 short MD simulations. Extended simulations of the wild type showed that the native complex formed in 500 ns among 4 of 53 simulations. In contrast, the C1188D mutant COM distributed broadly around the DNA and the native complex was not observed in any of the extended simulations. Simulations on the apo MLL1-CXXC domain further suggest that the wild type protein remained predominantly in an open form that closely resembles its structure in the native complex whereas C1188D mutant formed predominantly compact structures in which the N- terminal bends to D1188. This conformational switch hinders the formation of encounter complex, thus abolishes the recognition. Our study also provides clues to the study mechanism of recognition, by the CXXC domain from proteins like DNA methyltransferase and ten-eleven translocation enzymes. |
| Keywords: | CpG dinucleotides CXXC domain mixed lineage leukemia molecular dynamic simulation protein-DNA recognition |