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    Home > Biochemistry News > Biotechnology News > The latest article published by Peking University's Nature: Unraveling the structure of human PBAF chromatin remodeling complex bound to nucleosomes

    The latest article published by Peking University's Nature: Unraveling the structure of human PBAF chromatin remodeling complex bound to nucleosomes

    • Last Update: 2022-05-13
    • Source: Internet
    • Author: User
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    On April 27, 2022, the Joint Center for Life Sciences, the School of Life Sciences of Tsinghua University, the Advanced Innovation Center for Structural Biology, Zhucheng Chen, and the research team published online in the journal Nature entitled "Human-derived PBAF chromatin remodeling complex.
    "Structure of human PBAF chromatin remodeling complex bound to a nucleosome" research paper

    .
    This paper reports the structure of the human chromatin remodeling complex PBAF bound to nucleosomes in the active state, and reveals the assembly method of the 12-subunit PBAF complex and the mechanism for recognizing nucleosomes.
    The pathogenesis of human disease-associated mutations provides a theoretical framework

    .


      In eukaryotes, DNA is wrapped around histones to form nucleosomes, which are highly compressed to form chromatin
    .
    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

    .
    Therefore, the dynamic regulation of chromatin plays an important role in biology

    .
    Chromatin remodeling Snf2-family motor proteins utilize the energy of ATP to slide, eject, exchange, or depolymerize nucleosomes to achieve dynamic regulation of chromatin

    .


      BAF (BRG1-associated factors) and PBAF (polybromo-associated BRG1-associated factors) are chromatin remodeling complexes of the mammalian SWI/SNF family, they regulate chromatin structure and gene expression, and are widely involved in the development and differentiation of animal cells
    .
    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

    .
    BAF/PBAF is considered as a potential drug target for the treatment of major human diseases such as cancer

    .
    Therefore, the SWI/SNF family complexes have been widely concerned and studied

    .
    Although the BAF/PBAF complex has been identified as early as 1996, its assembly and chromatin remodeling mechanisms have remained unclear

    .
    Thanks to the development of cryo-electron microscopy, the high-resolution structures of yeast SWI/SNF family complexes and human BAF complexes have been reported in 2019 and 2020

    .
    However, issues such as how the PBAF complex is assembled, the mechanism of nucleosome recognition, and its differences with the BAF complex remain to be studied

    .
    In particular, the reported core motor subunit (SMARCA4/BRG1) of the BAF complex is inactive, and the pathogenic mechanisms of many disease-related mutations cannot be accurately resolved

    .


      Chen Zhucheng's research team has been deeply involved in the field of chromatin remodeling for a long time and has published a series of important results
    .
    On this basis, the research team overcame technical difficulties and made continuous breakthroughs, obtained high-quality PBAF complexes by in vitro recombination, and analyzed the high-resolution structure (3.
    4 angstroms) of PBAF-bound nucleosomes by cryo-electron microscopy

    .


      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 (actin-related protein) module with regulatory functions, and the SRM module (substrate) with chromatin targeting functions.
    recruitment module)

    .
    Among them, the nine auxiliary subunits of PBAF are shuttled and intertwined to form a three-lobed SRM module

    .
    These lobes are named according to their main biological functions: nucleosome-binding lobe (NBL), histone-tail-binding lobe (HBL) and DNA-binding lobe (HBL) lobe, DBL)

    .
    In contrast to BAF, HBL is unique to PBAF and contains specific subunits - PBRM1, PHF10 and BRD7

    .
    These subunits are organized together with 11 domains that bind histone tails

    .
    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

    .
    This work also proposes a possible mechanism by which PBAF binds transcription factors (TFs) and regulates gene expression

    .
    At the same time, this work also revealed the possible mechanism of ARID2, PBRM1 and other subunit site mutations to cause disease

    .

      Notably, the motor subunit SMARCA4 is active in the complex resolved in this study
    .
    In this structure, we can clearly see that the disease-associated mutations are mainly located around the highly conserved ATP-binding pocket, and the newly formed Brace-helix interface

    .
    The Brace-helix active interface mediates the interaction of two motor domains (Lobe1 and Lobe2), which is a key element for coupling ATP hydrolysis and nucleosome sliding.
    Found in Snf2

    .
    In their work at PABF, they found that multiple cancer-related SMARCA4 high-frequency mutation hotspots are located at the newly formed Brace-helix interface

    .
    Moreover, multiple mutations in the paralogous protein SMARCA2 associated with neurodevelopmental defects are also distributed at this interface

    .
    Biochemical experiments confirmed that mutations at these sites significantly reduced chromatin remodeling activity, suggesting a loss of BAF/PBAF complex function in patients

    .
    In addition, the high-quality electron microscope density revealed for the first time the mechanism by which the SnAc domain of the SMARCA4 subunit recognizes nucleosomes: SnAc recognizes the acidic pocket (AP) of nucleosomes through three "arginine anchors", promoting chromatin remodeling plastic activity

    .

      In conclusion, this work not only elucidates the mechanisms of PBAF complex assembly, nucleosome recognition, and chromatin remodeling, but also provides a theoretical basis for understanding the pathogenic mechanisms of BAF/PBAF-related mutations
    .
    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

    .

      Chen Zhu became the corresponding author of this article
    .
    Yuan Junjie, a 2019 doctoral student from the Life Center and the School of Life Sciences of Tsinghua University, and Chen Kangjing, a 2017 doctoral student, are the co-first authors of this article, and postdoctoral fellow Zhang Wenbo also participated in important work

    .
    This work has been strongly supported by the National Natural Science Foundation of China, the Ministry of Science and Technology Major Scientific Research Program Special Project, the Life Science Joint Center, the Beijing High-tech Innovation Center for Structural Biology, and the National Protein Science Research (Beijing) Facility Tsinghua Base

    .

     

    Original link:

     https:// 

     Structure and disease-associated mutations of the PBAF chromatin remodeling complex bound to nucleosomes 

    (a) Cryo-EM density map of PBAF-nucleosome complexes
    .
    (b) Structural model of the PBAF-nucleosome complex

    .
    (c) Model of the PBAF complex that recognizes nucleosomes and regulates chromatin structure

    .
    (d) Distribution of missense mutation sites in SMARCA4/2 associated with cancer and neurodevelopmental deficiency syndromes (data from COSMIC, cBioPortal and published literature)

    .
    Taking the SMARCA4 sequence as a reference, mark the high-frequency mutation sites; the corresponding amino acid residues of the SMARCA2 mutation are in []

    .
    (e) The disease-related mutation sites are mainly located around the "ATP pocket" and the "Brace interface".
    The enlarged image shows the distribution of high-frequency mutation sites at the Brace-helix interface.
    The biochemical experiments on the right show the mutations of R973 and R1243.
    Greatly reduces chromatin remodeling activity

    .


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