2020同步年報

Life Science 049 substitution of glutamine at position 772 in DNMT3B for arginine indeed makes the TRD loop less stable ( Fig. 2(h) ), as well as decreasing the processivity of methylation by DNMT3B ( Fig. 2(i) ). The authors summarized the structural impact of DNMT3B mutations related to ICF syndromes ( Fig. 2(j) ), which might help to understand the underlying mechanistic details of this pathogenesis. In summary, three conclusions have arisen according to the structural and biochemical data. (1) The human DNMT3B catalytic domain performs a specific CpG methylation. (2) DNMT3B has a flanking sequence preference different from that of DNMT3A, which is mediated by Lys777 and Asn779 located in the TRD loop. (3) DNMT3B adopts a TRD loop for processive methylation more stable than that of DNMT3A. Taken together, the mechanistic details of the methylation performed by DNMT3B are described through a structural elucidation of the DNMT3B catalytic domain. (Reported by Chao-Cheng Cho, Academia Sinica) This report features the work of Hanna S. Yuan and her col- leagues published in Nucleic Acid Res. 48 , 3949 (2020). Fig. 2 : (a) Detailed protein-DNA interactions in the DNMT3B–3L–DNA (CpGpG) complex, (b) DNMT3B–3L–DNA (CpGpT) complex and (c) DNMT3A–3L– DNA (ZpGpT) complex. (d) Methylation activities of DNMT3B and its mutants for 24-bp DNA containing CpGpG, CpGpA or CpGpT. (e) Superposi- tion of the DNA-free form of catalytic domains of DNMT3A (pink) and DNMT3B (green). (f) Hydrogen-bonded networks in the DNMT3B–3L–DNA complex and (g) DNMT3A–3L–DNA complex. (h) Superposition of crystal structures of wild-type and Q772R DNMT3B–3L complex. Disordered regions in the TRD loop of the wild-type and Q772R DNMT3B–3L complex are represented with dotted brown or cyan lines, respectively. (i) Methylation activities of the wild-type and Q772R DNMT3B–3L complex for DNA of varied lengths. (j) Structure of the DNMT3B–3L–DNA complex revealing the locations of the ICF syndrome-related mutations that are shown as magenta spheres (left). Magnified view of the mutations that might affect cofactor binding (right). [Reproduced from Ref. 7] TPS 05A Protein Microcrystallography TLS 15A1 IASW – Biopharmaceutical Protein Crys- tallography • Protein Crystallography • Biological Macromolecules, Protein Structures, Life Science References 1. R. Z. Jurkowska, T. P. Jurkowski, A. Jeltsch, ChemBioChem 12 , 206 (2011). 2. L. Yang, R. Rau, M. A. Goodell, Nat. Rev. Cancer 15 , 152 (2015). 3. A. H. Moarefi, F. Chédin, J. Mol. Biol. 409 , 758 (2011). 4. X. Guo, L. Wang, J. Li, Z. Ding, J. Xiao, X. Yin, S. He, P. Shi, L. Dong, G. Li, C. Tian, J. Wang, Y. Cong, Y. Xu, Nature 517 , 640 (2014). 5. D. Jia, R. Z. Jurkowska, X. Zhang, A. Jeltsch, X. Cheng, Nature 449 , 248 (2007). 6. Z.-M. Zhang, R. Lu, P. Wang, Y. Yu, D. Chen, L. Gao, S. Liu, D. Ji, S. B. Rothbart, Y. Wang, G. G. Wang, J. Song, Nature 554 , 387 (2018). 7. C.-C. Lin, Y.-P. Chen, W.-Z. Yang , J. C. K. Shen, H. S. Yuan, Nucleic Acids Res. 48 , 3949 (2020).