Profilin Directly Promotes Microtubule Growth through Residues Mutated in Amyotrophic Lateral Sclerosis.
Profilin Directly Promotes Microtubule Growth through Residues Mutated in Amyotrophic Lateral Sclerosis.
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叶酸蛋白直接通过在肌萎缩性侧索硬化症中突变的残基来促进微管生长。
DOI：
10.1016/j.cub.2017.10.002
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发表时间：
2017-11-20
期刊：
影响因子：
--
通讯作者：
Goode BL
中科院分区：
文献类型：
--
作者：
Henty-Ridilla JL;Juanes MA;Goode BL
Profilin是一种丰富的肌动蛋白单体结合蛋白，在体内具有重要的肌动蛋白调节作用。然而，Profilin也影响细胞中的微管动力学，这可能部分地通过其与继而结合微管的形成蛋白的相互作用来介导。肌萎缩侧索硬化症（ALS）患者中人Profilin-1（PFN 1）上的特定残基发生突变。然而，观察到一些ALS连锁PFN 1突变体不能改变细胞肌动蛋白组织或动力学或体外肌动蛋白单体亲和力一直令人困惑，因为Profilin最好理解为肌动蛋白调节剂。在这里，我们研究了Profilin对微管动力学的直接影响，以及PFN 1中ALS相关的突变是否会破坏这些功能。我们发现，人类，苍蝇，和酵母Profilin同源物都直接提高微管生长速度的几倍，在体外。微管刺激效应不受典型肌动蛋白或聚脯氨酸结合位点的突变的影响。相反，微管活性依赖于ALS患者中突变的Profilin上的特定表面残基。此外，微管效应减弱，增加浓度的肌动蛋白单体，表明肌动蛋白和微管之间的竞争结合Profilin。与这些生化观察结果一致，野生型PFN 1的表达水平增加两倍，而不是ALS连锁的PFN 1突变体，增加了细胞中微管的生长速率。总之，这些结果表明Profilin直接增强微管的生长速率。此外，他们认为PFN 1中ALS相关的突变可能会扰乱细胞微管动力学和/或肌动蛋白和微管细胞骨架之间的协调，导致运动神经元变性。
Profilin is an abundant actin monomer binding protein with critical actin regulatory roles in vivo. However, Profilin also influences microtubule dynamics in cells, which may be mediated in part through its interactions with Formins that in turn bind microtubules. Specific residues on human Profilin-1 (PFN1) are mutated in patients with amyotrophic lateral sclerosis (ALS). However, the observation that some ALS-linked PFN1 mutants fail to alter cellular actin organization or dynamics or in vitro actin-monomer affinity has been perplexing, given that Profilin is best understood as an actin regulator. Here, we investigated direct effects of Profilin on microtubule dynamics, and whether ALS-linked mutations in PFN1 disrupt such functions. We found that human, fly, and yeast Profilin homologs all directly enhance microtubule growth rate by several-fold in vitro. Microtubule stimulatory effects were unaffected by mutations in the canonical actin- or poly-proline-binding sites of Profilin. Instead, microtubule activities depended on specific surface residues on Profilin mutated in ALS patients. Further, microtubule effects were attenuated by increasing concentrations of actin monomers, suggesting competition between actin and microtubules for binding Profilin. Consistent with these biochemical observations, a two-fold increase in the expression level of wildtype PFN1, but not the ALS-linked PFN1 mutants, increased microtubule growth rates in cells. Together, these results demonstrate that Profilin directly enhances the growth rate of microtubules. Further, they suggest that ALS-linked mutations in PFN1 may perturb cellular microtubule dynamics, and/or the coordination between the actin and microtubule cytoskeletons, leading to motor neuron degeneration.
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DOI：
10.1126/science.aaf1709
发表时间：
2016-05-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Henty-Ridilla JL;Rankova A;Eskin JA;Kenny K;Goode BL
通讯作者：
Goode BL
Formin MDIA2独立于其肌动蛋白成核活性稳定微管。
影响因子：
7.8
作者：
Bartolini, Francesca;Moseley, James B.;Schmoranzer, Jan;Cassimeris, Lynne;Goode, Bruce L.;Gundersen, Gregg G.
通讯作者：
Gundersen, Gregg G.
影响因子：
21.3
作者：
Morton, WM;Ayscough, KR;McLaughlin, PJ
通讯作者：
McLaughlin, PJ
影响因子：
50.3
作者：
Mouneimne G;Hansen SD;Selfors LM;Petrak L;Hickey MM;Gallegos LL;Simpson KJ;Lim J;Gertler FB;Hartwig JH;Mullins RD;Brugge JS
通讯作者：
Brugge JS
影响因子：
11.8
作者：
Rotty, Jeremy D.;Wu, Congying;Haynes, Elizabeth M.;Suarez, Cristian;Winkelman, Jonathan D.;Johnson, Heath E.;Haugh, Jason M.;Kovar, David R.;Bear, James E.
通讯作者：
Bear, James E.