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    Home > Biochemistry News > Biotechnology News > A new mechanism for the regulation of histone acetyl transferenzyme activity is revealed.

    A new mechanism for the regulation of histone acetyl transferenzyme activity is revealed.

    • Last Update: 2020-08-08
    • Source: Internet
    • Author: User
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    On August 9th, Xu Ruiming of the Institute of Biophysics of the Chinese Academy of Sciences, in collaboration with Zhang Zhiguo's team at Columbia University in the United States, published in Cell on multisite-based-based recognition in Asf1-dependent acetylation of histone H3K56 by Rtt109.
    the work revealed for the first time the molecular mechanism of histone partners regulating histone modification enzyme activity by analyzing the crystal structure of the fungus-specific histone acetyl transferet Rtt109 and the active regulator Asf1 and the substrate H3-H4 complex, combining biochemical and genetic experiments.
    this is the structure of the first histone-modified enzyme and complete substrate complex in the field of chromatin.
    nucleosomes are the basic structural units of eyrenucleosome chromatin, formed by the entanglement of about 146 bp of DNA in the core histone octapolymer.
    dynamic changes in the local structure of chromatin affect many important life activity processes, such as DNA replication, RNA transcription, DNA damage repair, recombination, and so on.
    histone-translated modification is an important factor affecting chromatin structure, these modifications mainly occur on the tail at the end of histones, including methylation, acetylation, phosphoryelation and unonate.
    the crystal structure of the Rtt109-Asf1-H3-H4 quadcomplex and the acetyl coenzyme A complex of the ilysidine donor.
    The N-end alpha-helix of H3 is opened to form a flexible loop region; Asf1 does not interact directly with Rtt109, but forms beta-folding plates between one of the beta-strands at its C end and the C end of the histone H4, stabilizing a key fragment at the end of H4, leaving the substrate in a more catalytic configuration and thus promoting the activity of Rtt109.
    2007, Zhang Zhiguo and Xu Ruiming's team collaborated to report the phenomenon of histone H3K56 bit acetylation, and identified the fungus-specific acetyl transferase Rtt109 as the enzyme that catalyzed the modification.
    this is not the same as all previously found positions located in the hetone N-end irregular tail, H3K56 is located in h3's N-end alpha-helix structure domain, near the import and export of nucleosome DNA.
    cells lacking H3K56 acetylation modification are prone to DNA damage and chromatin rearrangement, which is related to the role of modification in the stability of DNA replication forks and the maturation of nucleosomes.
    Zhang Zhiguo and Xu Ruiming's team further studied the regulation of the activity of two histone partners Asf1 and Vps75 on Rtt109 enzyme activity, and in vitro experiments showed that both histone partners could form a complex with Rtt109, but Vps75 mainly promoted the catalytic activity of Rtt109 at H3K9 and H3K27 sites, and Asf1 was an important regulator of H3K56.
    the assembly of the Rtt109 and Asf1 in vitro complexes is difficult, and it takes a lot of attempt to eliminate the interference of the Vps75.
    Xu Ruiming and Zhang Zhiguo's team after more than ten years of efforts, cleverly through the lack of Vps75 binding site of the tobacco-cranked mold Rtt109, with yeast Asf1 and substrate histone H3-H4 assembled a good complex, and analysis of the quadrine and acetyl donor CoA composite crystal structure.
    can be seen from the structure, the H3K56 is located in the N-end alpha-helix is opened, forming a flexible loop area, the loop area is bound around the active pocket of Rtt109, so that the Side Chain of the H3K56 extends into the active pocket.
    Although histone mate Asf1 is essential for H3K56 modification, there is no direct interaction between Asf1 and Rtt109.
    Asf1 forms a beta-folding chip between one of its C-ends and the C end of histone H4, stabilizing a key fragment at the end of H4, leaving the substrate in a more catalytic conformation and thus promoting the activity of Rtt109.
    this structural characteristic has been confirmed by further biochemical and genetic experiments as a necessary condition for Rtt109 to function, and the interaction of Rtt109 with the core helical structure of histone H3 is also necessary for its activity.
    this work for the first time reveals the complex regulatory mechanism of histone modifier's multi-kilo and polystate identification sites, which provides an important basis for understanding the substrate identification and activity regulation mechanism of this class of acetylationase, and also provides a clue and basis for the research of antifungal drugs targeting Rtt109. The research work of
    was completed by Xu Ruiming's research team in cooperation with Zhang Zhiguo's team.
    Xu Ruiming and Zhang Zhiguo are co-authors of the paper, and Xu Ruiming's team doctoral students Zhang Lin and Zhang Zhiguo's team, Serra-Cardona Albert, are co-first authors of the paper.
    research has been supported by the Innovation Group of the National Natural Science Foundation of China, major international cooperation projects, the National Key Basic Research and Development Plan (973 Plan), the National Key Research and Development Program, the Strategic Leading Science and Technology Project of the Chinese Academy of Sciences (Class B) and the Beijing Natural Science Foundation.
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