Modeling a disease-correlated tubulin mutation in budding yeast reveals insight into MAP-mediated dynein function.
Modeling a disease-correlated tubulin mutation in budding yeast reveals insight into MAP-mediated dynein function.
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DOI：
10.1091/mbc.e21-05-0237
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发表时间：
2021-10-01
影响因子：
3.3
通讯作者：
Boscheron C
中科院分区：
文献类型：
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作者：
Denarier E;Ecklund KH;Berthier G;Favier A;O'Toole ET;Gory-Fauré S;De Macedo L;Delphin C;Andrieux A;Markus SM;Boscheron C
编码α-和β-微管蛋白的基因突变是许多神经系统疾病的基础，最明显的是皮质发育畸形。除了揭示疾病病因的分子基础外，研究此类突变还可以深入了解微管功能和微管效应子大家族的作用。在这项研究中，我们使用芽殖酵母来模拟一个这样的突变-α-微管蛋白中的Gly 436 Arg，这是导致皮质发育畸形的原因，以了解它如何影响微管功能在一个简单的真核系统中。使用体外和体内方法的组合，包括活细胞成像和电子断层扫描，我们发现突变微管蛋白被纳入微管，导致α-微管蛋白同种型使用的转变，并显着增强动力蛋白活性，导致纺锤体定位缺陷。我们发现，后者的表型的基础是一个受损的相互作用之间的She 1-动力蛋白转运蛋白和突变的微管。除了揭示细胞中α-微管蛋白同种型利用的自然平衡外，我们的研究结果还提供了微管蛋白突变导致微管和动力蛋白调节剂之间相互作用受损的证据，并揭示了可能导致神经发育疾病的机制。
Mutations in the genes that encode α- and β-tubulin underlie many neurological diseases, most notably malformations in cortical development. In addition to revealing the molecular basis for disease etiology, studying such mutations can provide insight into microtubule function and the role of the large family of microtubule effectors. In this study, we use budding yeast to model one such mutation—Gly436Arg in α-tubulin, which is causative of malformations in cortical development—in order to understand how it impacts microtubule function in a simple eukaryotic system. Using a combination of in vitro and in vivo methodologies, including live cell imaging and electron tomography, we find that the mutant tubulin is incorporated into microtubules, causes a shift in α-tubulin isotype usage, and dramatically enhances dynein activity, which leads to spindle-positioning defects. We find that the basis for the latter phenotype is an impaired interaction between She1—a dynein inhibitor—and the mutant microtubules. In addition to revealing the natural balance of α-tubulin isotype utilization in cells, our results provide evidence of an impaired interaction between microtubules and a dynein regulator as a consequence of a tubulin mutation and sheds light on a mechanism that may be causative of neurodevelopmental diseases.
DOI：
10.1083/jcb.201701094
发表时间：
2017-09-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Zhu Y;An X;Tomaszewski A;Hepler PK;Lee WL
通讯作者：
Lee WL