Tau directs intracellular trafficking by regulating the forces exerted by kinesin and dynein teams.
Tau directs intracellular trafficking by regulating the forces exerted by kinesin and dynein teams.
复制标题
Tau通过调节动力蛋白和动力蛋白团队施加的力来指导细胞内贩运。
DOI：
10.1111/tra.12537
复制
发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Hendricks AG
中科院分区：
文献类型：
--
作者：
Chaudhary AR;Berger F;Berger CL;Hendricks AG
细胞器、蛋白质和 mRNA 通过正端定向驱动蛋白和负端定向动力蛋白马达沿着微管双向运输。微管由微管相关蛋白 (MAP) 装饰，微管相关蛋白 (MAP) 组织细胞骨架、调节微管动力学并调节运动蛋白和微管之间的相互作用以指导细胞内运输。 Tau 是一种神经元 MAP，可稳定轴突微管并将其交联成束。 tau 蛋白失调会导致一系列称为 tau 蛋白病的神经退行性疾病，包括阿尔茨海默病 (AD)。 Tau 通过充当微管上的障碍来降低驱动蛋白和动力蛋白的持续合成能力。单分子检测表明，kinesin-1 比 kinesin-2 或动力蛋白受到更强烈的抑制，这表明 tau 可能在空间上调节特定马达的活动。为了研究 tau 在调节双向运输中的作用，我们分离了由驱动蛋白 1、驱动蛋白 2 和动力蛋白驱动的吞噬体，并重建了它们沿微管的运动。我们发现 tau 蛋白以剂量依赖性方式使双向运动偏向微管负端。光学捕获测量表明，tau 通过抑制相反的驱动蛋白马达来增加动力蛋白施加的力的大小和频率。数学模型表明，tau 通过差异调节驱动蛋白 1、驱动蛋白 2 和动力蛋白的持续合成能力来控制细胞内货物的方向偏差。总而言之，这些结果表明 tau 以运动特异性方式调节运动以指导细胞内运输，并表明 tau 失调可能通过破坏正端和负端定向运输的平衡而导致神经退行性变。 我们分离了内源性货物以及驱动蛋白-1、驱动蛋白-2 和动力蛋白马达的补充，并在体外重建了它们的双向运动。我们发现 tau 是一种微管相关蛋白，可稳定神经元轴突中的微管，通过调节驱动蛋白和动力蛋白团队施加的力的平衡，将双向货物引导至微管负端。这些结果提出了通过调节相对运动团队的相对活动来调节细胞内货物运输的一般机制。
Organelles, proteins, and mRNA are transported bidirectionally along microtubules by plus-end directed kinesin and minus-end directed dynein motors. Microtubules are decorated by microtubule-associated proteins (MAPs) that organize the cytoskeleton, regulate microtubule dynamics and modulate the interaction between motor proteins and microtubules to direct intracellular transport. Tau is a neuronal MAP that stabilizes axonal microtubules and crosslinks them into bundles. Dysregulation of tau leads to a range of neurodegenerative diseases known as tauopathies including Alzheimer’s disease (AD). Tau reduces the processivity of kinesin and dynein by acting as an obstacle on the microtubule. Single-molecule assays indicate that kinesin-1 is more strongly inhibited than kinesin-2 or dynein, suggesting tau might act to spatially modulate the activity of specific motors. To investigate the role of tau in regulating bidirectional transport, we isolated phagosomes driven by kinesin-1, kinesin-2, and dynein and reconstituted their motility along microtubules. We find that tau biases bidirectional motility towards the microtubule minus-end in a dose-dependent manner. Optical trapping measurements show that tau increases the magnitude and frequency of forces exerted by dynein through inhibiting opposing kinesin motors. Mathematical modeling indicates that tau controls the directional bias of intracellular cargoes through differentially tuning the processivity of kinesin-1, kinesin-2, and dynein. Taken together, these results demonstrate that tau modulates motility in a motor-specific manner to direct intracellular transport, and suggests that dysregulation of tau might contribute to neurodegeneration by disrupting the balance of plus- and minus-end directed transport. We isolated endogenous cargoes, along with a complement of kinesin-1, kinesin-2, and dynein motors, and reconstituted their bidirectional motility in vitro. We find that tau, a microtubule-associated protein that stabilizes microtubules in neuronal axons, directs bidirectional cargoes towards the microtubule minus end by tuning the balance of forces exerted by kinesin and dynein teams. These results suggest a general mechanism for regulating the transport of intracellular cargoes through modulating the relative activity of opposing motor teams.
登录
查看更多内容
DOI：
10.1083/jcb.200908075
发表时间：
2009-12-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ally S;Larson AG;Barlan K;Rice SE;Gelfand VI
通讯作者：
Gelfand VI
影响因子：
3.3
作者：
Barkus, Rosemarie V.;Klyachko, Olga;Saxton, William M.
通讯作者：
Saxton, William M.
DOI：
10.1083/jcb.137.1.113
发表时间：
1997-04-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Blocker A;Severin FF;Burkhardt JK;Bingham JB;Yu H;Olivo JC;Schroer TA;Hyman AA;Griffiths G
通讯作者：
Griffiths G
DOI：
10.1073/pnas.1215462109
发表时间：
2012-11-06
影响因子：
11.1
作者：
Hendricks, Adam G.;Holzbaur, Erika L. F.;Goldman, Yale E.
通讯作者：
Goldman, Yale E.
影响因子：
9.2
作者：
Andreasson, Johan O. L.;Shastry, Shankar;Hancock, William O.;Block, Steven M.
通讯作者：
Block, Steven M.