Dimerization activates the Inversin complex in C. elegans.

IF 3.1 3区 生物学 Q3 CELL BIOLOGY Molecular Biology of the Cell Pub Date : 2024-10-01 Epub Date: 2024-08-07 DOI:10.1091/mbc.E24-05-0218
Erika Beyrent, Derek T Wei, Gwendolyn M Beacham, Sangwoo Park, Jian Zheng, Matthew J Paszek, Gunther Hollopeter
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Abstract

Genetic, colocalization, and biochemical studies suggest that the ankyrin repeat-containing proteins Inversin (INVS) and ANKS6 function with the NEK8 kinase to control tissue patterning and maintain organ physiology. It is unknown whether these three proteins assemble into a static "Inversin complex" or one that adopts multiple bioactive forms. Through the characterization of hyperactive alleles in C. elegans, we discovered that the Inversin complex is activated by dimerization. Genome engineering of an RFP tag onto the nematode homologues of INVS (MLT-4) and NEK8 (NEKL-2) induced a gain-of-function, cyst-like phenotype that was suppressed by monomerization of the fluorescent tag. Stimulated dimerization of MLT-4 or NEKL-2 using optogenetics was sufficient to recapitulate the phenotype of a constitutively active Inversin complex. Further, dimerization of NEKL-2 bypassed a lethal MLT-4 mutant, demonstrating that the dimeric form is required for function. We propose that dynamic switching between at least two functionally distinct states - an active dimer and an inactive monomer - gates the output of the Inversin complex.

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二聚化激活了秀丽隐杆线虫中的 Inversin 复合物。
遗传、共定位和生化研究表明,含霉素重复蛋白 Inversin(INVS)和 ANKS6 与 NEK8 激酶共同发挥作用,控制组织形态并维持器官生理机能。目前还不清楚这三种蛋白是组装成一个静态的 "Inversin 复合物",还是一个具有多种生物活性的复合物。通过对 elegans 中超常等位基因的鉴定,我们发现 Inversin 复合物是通过二聚化激活的。将 RFP 标记植入线虫 INVS(MLT-4)和 NEK8(NEKL-2)的同源物基因组工程中,会诱导出一种功能增益的囊状表型,这种表型会被荧光标记的单聚化所抑制。使用光遗传学方法刺激 MLT-4 或 NEKL-2 的二聚化足以重现组成型活性 Inversin 复合物的表型。此外,NEKL-2的二聚化绕过了致命的MLT-4突变体,证明二聚形式是功能所必需的。我们认为,至少有两种功能上不同的状态--活性二聚体和非活性单体--之间的动态切换控制着 Inversin 复合物的输出。
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来源期刊
Molecular Biology of the Cell
Molecular Biology of the Cell 生物-细胞生物学
CiteScore
6.00
自引率
6.10%
发文量
402
审稿时长
2 months
期刊介绍: MBoC publishes research articles that present conceptual advances of broad interest and significance within all areas of cell, molecular, and developmental biology. We welcome manuscripts that describe advances with applications across topics including but not limited to: cell growth and division; nuclear and cytoskeletal processes; membrane trafficking and autophagy; organelle biology; quantitative cell biology; physical cell biology and mechanobiology; cell signaling; stem cell biology and development; cancer biology; cellular immunology and microbial pathogenesis; cellular neurobiology; prokaryotic cell biology; and cell biology of disease.
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