Abstract
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 hSNF5171–258 and BAF155SWIRM are both monomeric in solution and they form a heterodimer. NMR data and crystal structure of the hSNF5171–258/BAF155SWIRM complex further reveal a unique binding interface, which involves a coil-to-helix transition upon protein binding. The newly formed αN helix of hSNF5171–258 interacts with the β2–α1 loop of hSNF5 via hydrogen bonds and it also displays a hydrophobic interaction with BAF155SWIRM. Therefore, the N-terminal region of hSNF5171–258 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 N-terminal loop region of hSNF5.
Highlights
Chromatin remodeling is a process that changes the chromatin structure between a condensed state and a transcriptionally accessible state, which is essential for the control of gene expression [1,2,3,4]
Using size exclusion chromatography (SEC), we found that hSNF5171–258 elutes at a higher molecular weight than the monomer fraction, whereas BAF155SWIRM elutes in the monomer fraction (Figure 2A,B)
Line widths of the amide resonances of His171, Glu178, Asn179, Ser181, and Gln182 residues in hSNF5171–258 are unusually broadened upon BAF155SWIRM binding, which suggested that the N-terminal loop region of hSNF5171–258 plays an important role in this interaction (Figure 3C)
Summary
Chromatin remodeling is a process that changes the chromatin structure between a condensed state and a transcriptionally accessible state, which is essential for the control of gene expression [1,2,3,4]. SWI/SNF (SWItch/Sucrose Non-Fermentable) is an evolutionarily conserved chromatin-remodeling complex that couples ATP hydrolysis with chromatin structure rearrangement. BAF155 (a human homologue of yeast SWI3) is another core component of the SWI/SNF complex that displays ATPase activity [27,28,29,30]. This protein protects the SWI/SNF complex from proteasomal degradation and it directs the nuclear localization of the complex [29,31,32]. Our structure reveals the detailed binding interface between hSNF5 and BAF155 and it highlights a novel folding-upon-binding mechanism in the assembly of this chromatin-remodeling complex
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