The latest "Nature": Uncovering the structure and mechanism of key chromatin remodeling complexes

In eukaryotes, DNA wraps around histones to form nucleosomes, which are highly compressed to form chromatin
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This form ensures the stability of the genome on the one hand, and hinders life activities such as the replication of genetic information, transcription and DNA damage repair on the other
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Therefore, the dynamic regulation of chromatin plays an important role in biology
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During regulation, chromatin remodeling is critical for SNF2-family motor proteins, which use the energy of ATP to slide, eject, exchange or disaggregate nucleosomes
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Among them, BAF and PBAF are chromatin remodeling complexes of the mammalian SWI/SNF family.
They can regulate chromatin structure and gene expression, and are widely involved in the development and differentiation of animal cells
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In recent years, with the development of high-throughput sequencing technology, researchers have found that mutations in the BAF/PBAF complex are associated with more than 20% of cancers and various neurodevelopmental defects
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Moreover, BAF/PBAF is considered as a potential drug target for the treatment of major human diseases such as cancer.
Therefore, analyzing the assembly method of PBAF complexes and identifying the mechanism of nucleosomes has become the key point of research
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On April 27, the research team of Professor Chen Zhucheng from the School of Life Sciences of Tsinghua University/High-tech Innovation Center for Structural Biology/Tsinghua-Peking University Life Science Joint Center published a paper in "Nature", which provides insights into the pathogenic mechanism of many human disease-related mutations.
the theoretical framework
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The latest research reports the structure of the human chromatin remodeling complex PBAF bound to nucleosomes in the active state, revealing the assembly method of the PBAF complex composed of 12 subunits, and the mechanism of nucleosome recognition
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The research team obtained high-quality PBAF complexes by in vitro recombination, and analyzed the high-resolution structure of PBAF-bound nucleosomes using cryo-electron microscopy
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According to the new study, the 12 subunits of the PBAF complex can be divided into three modules according to their different functions: the motor module with catalytic activity, the ARP module with regulatory function, and the SRM module with chromatin targeting function
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Among them, the nine auxiliary subunits of PBAF are shuttled and intertwined to form a three-lobed SRM module
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These leaves are named according to their main biological functions: nucleosome-binding leaf (NBL), histone tail-binding leaf (HBL) and DNA-binding leaf (DBL)
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Compared with BAF, HBL is a PBAF-specific structure, containing specific subunits—PBRM1, PHF10 and BRD7
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These subunits are organized together with 11 domains that bind histone tails
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The researchers believe that this is equivalent to a super-histone recognition submodule, which is beneficial for the PBAF complex to sense chromatin signals more efficiently in the body and play a chromatin remodeling function
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In addition, the new study found that the motor subunit SMARCA4 in the complex is active
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In this structure, disease-associated mutations are primarily located around the highly conserved ATP-binding pocket, and the newly formed Brace-helix interface
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Multiple cancer-related SMARCA4 high-frequency mutation hotspots are located at the newly formed Brace-helix interface
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Moreover, multiple mutations in the paralogous protein SMARCA2, which are associated with neurodevelopmental defects, also occur at this interface
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The research team confirmed through biochemical experiments that mutations at these sites significantly reduced chromatin remodeling activity, suggesting what may be the problem with the loss of function of the BAF/PBAF complex in certain disease states
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The new study not only elucidates the mechanism of PBAF complex assembly, nucleosome recognition, and chromatin remodeling, but also provides a theoretical basis for understanding the pathogenic mechanism of BAF/PBAF-related mutations
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This discovery is conducive to understanding the mechanism of chromatin remodeling at the chromatin level, and will also promote the development of targeted drugs for related diseases in the future
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