Merlin tumor suppressor function is regulated by PIP2-mediated dimerization.
Merlin tumor suppressor function is regulated by PIP2-mediated dimerization.
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Merlin 肿瘤抑制功能受 PIP2 介导的二聚化调节。
DOI：
10.1371/journal.pone.0281876
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发表时间：
2023
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
神经纤维瘤病2型是一种遗传性疾病，其特征是颅神经和周围神经的schwann细胞肿瘤。终端域的变化。构象的Merlin活性已显示为二聚体，但是我们使用了基于纳米的结合测定法的调节和函数。彼此衍生的患者和结构突变体表明，二聚化控制着与特定的结合伙伴的相互作用，包括河马途径成分肿瘤抑制活性。公开会议Merlin是一个二聚体，代表了Merlin功能的新范式，对旨在补偿Merlin损失的疗法的开发产生了影响。
Neurofibromatosis Type 2 is an inherited disease characterized by Schwann cell tumors of cranial and peripheral nerves. The NF2 gene encodes Merlin, a member of the ERM family consisting of an N-terminal FERM domain, a central α-helical region, and a C-terminal domain. Changes in the intermolecular FERM-CTD interaction allow Merlin to transition between an open, FERM accessible conformation and a closed, FERM-inaccessible conformation, modulating Merlin activity. Merlin has been shown to dimerize, but the regulation and function Merlin dimerization is not clear. We used a nanobody based binding assay to show that Merlin dimerizes via a FERM-FERM interaction, orientated with each C-terminus close to each other. Patient derived and structural mutants show that dimerization controls interactions with specific binding partners, including HIPPO pathway components, and correlates with tumor suppressor activity. Gel filtration experiments showed that dimerization occurs after a PIP2 mediated transition from closed to open conformation monomers. This process requires the first 18 amino acids of the FERM domain and is inhibited by phosphorylation at serine 518. The discovery that active, open conformation Merlin is a dimer represents a new paradigm for Merlin function with implications for the development of therapies designed to compensate for Merlin loss.
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影响因子：
4.8
作者：
Alfthan, K;Heiska, L;Carpen, O
通讯作者：
Carpen, O
影响因子：
4.8
作者：
Kissil, JL;Johnson, KC;Jacks, T
通讯作者：
Jacks, T
影响因子：
5.6
作者：
Ali Khajeh J;Ju JH;Atchiba M;Allaire M;Stanley C;Heller WT;Callaway DJ;Bu Z
通讯作者：
Bu Z
影响因子：
8.8
作者：
Furukawa, Kana T.;Yamashita, Kazunari;Ohno, Shigeo
通讯作者：
Ohno, Shigeo
影响因子：
3.4
作者：
Armstrong, JK;Wenby, RB;Fisher, TC
通讯作者：
Fisher, TC