Structural Biochemistry & Molecular Biophysics Laboratory, Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-740, Korea.
Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea.
Int J Mol Sci. 2020 Apr 1;21(7):2452. doi: 10.3390/ijms21072452.
Human SNF5 and BAF155 constitute the core subunit of multi-protein SWI/SNF chromatin-remodeling complexes that are required for ATP-dependent nucleosome mobility and transcriptional control. Human SNF5 (hSNF5) utilizes its repeat 1 (RPT1) domain to associate with the SWIRM domain of BAF155. Here, we employed X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, and various biophysical methods in order to investigate the detailed binding mechanism between hSNF5 and BAF155. Multi-angle light scattering data clearly indicate that hSNF5 and BAF155 are both monomeric in solution and they form a heterodimer. NMR data and crystal structure of the hSNF5/BAF155 complex further reveal a unique binding interface, which involves a coil-to-helix transition upon protein binding. The newly formed α helix of hSNF5 interacts with the β2-α1 loop of hSNF5 via hydrogen bonds and it also displays a hydrophobic interaction with BAF155. Therefore, the -terminal region of hSNF5 plays an important role in tumorigenesis and our data will provide a structural clue for the pathogenesis of Rhabdoid tumors and malignant melanomas that originate from mutations in the -terminal loop region of hSNF5.
人类 SNF5 和 BAF155 构成了多蛋白 SWI/SNF 染色质重塑复合物的核心亚基，该复合物对于 ATP 依赖性核小体迁移和转录控制是必需的。人类 SNF5（hSNF5）利用其重复 1（RPT1）结构域与 BAF155 的 SWIRM 结构域结合。在这里，我们采用 X 射线晶体学、核磁共振（NMR）光谱学和各种生物物理方法来研究 hSNF5 和 BAF155 之间的详细结合机制。多角度光散射数据清楚地表明，hSNF5 和 BAF155 在溶液中均为单体，并且它们形成异源二聚体。NMR 数据和 hSNF5/BAF155 复合物的晶体结构进一步揭示了一个独特的结合界面，该界面涉及蛋白结合时的螺旋到卷曲的转变。hSNF5 的新形成的α螺旋通过氢键与 hSNF5 的β2-α1 环相互作用，并且与 BAF155 也显示出疏水相互作用。因此，hSNF5 的 C 端区域在肿瘤发生中起重要作用，并且我们的数据将为源自 hSNF5 的 C 端环区域突变的横纹肌肉瘤和恶性黑色素瘤的发病机制提供结构线索。
