Two-step colocalization of MORC3 with PML nuclear bodies
Two-step colocalization of MORC3 with PML nuclear bodies
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DOI：
10.1242/jcs.063586
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发表时间：
2010-06-15
影响因子：
4
通讯作者：
Inoue, Norimitsu
中科院分区：
文献类型：
--
作者：
Mimura, Yasuhiro;Takahashi, Keiko;Inoue, Norimitsu
许多功能子结构域，包括早幼粒细胞白血病核体 (PML NB)，都是在哺乳动物细胞核中形成的。各种蛋白质以 PML 依赖性方式组成型或瞬时积累在 PML NB 中。 MORC3（小睾丸家族 CW 型锌指 3），也称为 NXP2，由 GHL-ATPase、CW 型锌指和卷曲螺旋结构域组成，定位于 PML NB，在那里招募并激活 p53 以诱导细胞衰老。有趣的是，我们发现MORC3可以在小鼠造血细胞甚至Pml缺陷细胞中形成PML独立的核结构域（ND）。在这里，我们表明 MORC3 通过两步分子机制与 PML 共定位：通过 ATP 循环形成独立于 PML 的 MORC3 ND，以及 MORC3 通过 SUMO1-SUMO 相互作用基序 (SIM) 与 PML 关联。与 GHL-ATPase 家族的其他成员类似，MORC3 的功能是“分子钳”。 ATP 结合诱导 MORC3 构象变化，导致 MORC3 ND 的形成，随后 ATP 水解介导 MORC3 扩散并与核基质结合。 MORC3 可能通过 CW 结构域将 DNA 或核小体夹在 MORC3 ND 中。此外，MORC3 在五个位点的 SUMO 化参与了 MORC3 与 PML 的关联，并且 SUMO1 未修饰的 MORC3 形成独立于 PML 的 ND。
Many functional subdomains, including promyelocytic leukemia nuclear bodies (PML NBs), are formed in the mammalian nucleus. Various proteins are constitutively or transiently accumulated in PML NBs in a PML-dependent manner. MORC3 (microrchidia family CW-type zinc-finger 3), also known as NXP2, which consists of GHL-ATPase, a CW-type zinc-finger and coiled-coil domains, is localized in PML NBs, where it recruits and activates p53 to induce cellular senescence. Interestingly, we found that MORC3 can form PML-independent nuclear domains (NDs) in mouse hematopoietic cells and even in Pml-deficient cells. Here, we show that MORC3 colocalizes with PML by a two-step molecular mechanism: the PML-independent formation of MORC3 NDs by the ATPase cycle, and the association of MORC3 with PML via the SUMO1-SUMO-interacting motif (SIM). Similarly to other members of the GHL-ATPase family, MORC3 functions as a 'molecular clamp'. ATP binding induces conformational changes in MORC3, leading to the formation of MORC3 NDs, and subsequent ATP hydrolysis mediates the diffusion and binding of MORC3 to the nuclear matrix. MORC3 might clamp DNA or nucleosomes in MORC3 NDs via the CW domain. Furthermore, the SUMOylation of MORC3 at five sites was involved in the association of MORC3 with PML, and SUMO1-unmodified MORC3 formed NDs independently of PML.