Molecular mechanism of the MORC4 ATPase activation.
Molecular mechanism of the MORC4 ATPase activation.
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DOI：
10.1038/s41467-020-19278-8
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发表时间：
2020-10-29
影响因子：
16.6
通讯作者：
Kutateladze TG
中科院分区：
文献类型：
--
作者：
Tencer AH;Cox KL;Wright GM;Zhang Y;Petell CJ;Klein BJ;Strahl BD;Black JC;Poirier MG;Kutateladze TG
人小睾吸虫4（MORC 4）与急性和慢性胰腺炎，炎症性疾病和癌症有关，但它在很大程度上仍然没有特征。在这里，我们描述了MORC 4的结构-功能关系，并定义MORC 4激活的分子机制。酶促和结合分析表明，MORC 4具有ATP酶活性，这取决于ATP酶结构域和CW结构域的DNA结合功能。MORC 4的ATPaseCW盒的晶体结构和诱变研究表明，CW的DNA结合位点和组蛋白/ATP酶结合位点位于结构域的相对侧。ATP酶和CW结构域在M0 RC 4与核小体核心颗粒（NCP）的结合中协作，增强DNA包裹在组蛋白核心周围并阻碍DNA相关蛋白（例如转录因子）与NCP的结合。在细胞中，MORC 4介导细胞核中核体的形成，并在细胞周期的S期进展中发挥作用，这两种功能都需要MORC 4的CW和催化活性。我们的研究结果强调了MORC 4激活的机制，这与在其他MORC家族成员中观察到的作用机制明显不同。人微丝蚴4（M0 RC 4）ATP酶与急性和慢性胰腺炎、炎性疾病和癌症有关。在这里，作者描述了MORC 4的结构-功能关系，并定义了MORC 4激活的分子机制。
Human Microrchidia 4 (MORC4) is associated with acute and chronic pancreatitis, inflammatory disorders and cancer but it remains largely uncharacterized. Here, we describe the structure–function relationship of MORC4 and define the molecular mechanism for MORC4 activation. Enzymatic and binding assays reveal that MORC4 has ATPase activity, which is dependent on DNA-binding functions of both the ATPase domain and CW domain of MORC4. The crystal structure of the ATPaseCW cassette of MORC4 and mutagenesis studies show that the DNA-binding site and the histone/ATPase binding site of CW are located on the opposite sides of the domain. The ATPase and CW domains cooperate in binding of MORC4 to the nucleosome core particle (NCP), enhancing the DNA wrapping around the histone core and impeding binding of DNA-associated proteins, such as transcription factors, to the NCP. In cells, MORC4 mediates formation of nuclear bodies in the nucleus and has a role in the progression of S-phase of the cell cycle, and both these functions require CW and catalytic activity of MORC4. Our findings highlight the mechanism for MORC4 activation, which is distinctly different from the mechanisms of action observed in other MORC family members. Human Microrchidia 4 (MORC4) ATPase has been implicated in acute and chronic pancreatitis, inflammatory disorders and cancer. Here the authors describe the structure–function relationship of MORC4 and define the molecular mechanism for MORC4 activation.
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影响因子：
14.9
作者：
Gibson MD;Gatchalian J;Slater A;Kutateladze TG;Poirier MG
通讯作者：
Poirier MG
影响因子：
14.9
作者：
Klein BJ;Muthurajan UM;Lalonde ME;Gibson MD;Andrews FH;Hepler M;Machida S;Yan K;Kurumizaka H;Poirier MG;Côté J;Luger K;Kutateladze TG
通讯作者：
Kutateladze TG
影响因子：
16.8
作者：
Musselman, Catherine A.;Lalonde, Marie-Eve;Cote, Jacques;Kutateladze, Tatiana G.
通讯作者：
Kutateladze, Tatiana G.
影响因子：
6.5
作者：
Liggins, Amanda P.;Cooper, Christopher D. O.;Banham, Alison H.
通讯作者：
Banham, Alison H.
影响因子：
3.6
作者：
Weiss, Frank Ulrich;Hesselbarth, Nico;Rosendahl, Jonas
通讯作者：
Rosendahl, Jonas