ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function.
ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function.
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DOI：
10.1016/j.celrep.2022.110598
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发表时间：
2022-04-05
期刊：
影响因子：
8.8
通讯作者：
Landers, John E.
中科院分区：
文献类型：
--
作者：
Baron, Desiree M.;Fenton, Adam R.;Saez-Atienzar, Sara;Giampetruzzi, Anthony;Sreeram, Aparna;Shankaracharya;Keagle, Pamela J.;Doocy, Victoria R.;Smith, Nathan J.;Danielson, Eric W.;Andresano, Megan;McCormack, Mary C.;Garcia, Jaqueline;Bercier, Valerie;Van den Bosch, Ludo;Brent, Jonathan R.;Fallini, Claudia;Traynor, Bryan J.;Holzbaur, Erika L. F.;Landers, John E.
ALS相关基因KIF 5A突变导致27号外显子跳跃（KIF 5A Δ Exon 27），编码一个新的39个氨基酸残基的蛋白质。在这里，我们报告ALS连锁突变KIF 5A的表达导致运动活动失调，细胞定位错误，轴突运输改变，神经元存活减少。单分子分析显示，突变KIF 5A的C末端改变导致组成型活性状态。此外，突变体KIF 5A具有改变的蛋白质和RNA相互作用，并且其表达导致改变的基因表达/剪接。综上所述，我们的数据支持这一假设，即致病性ALS突变导致细胞内运动KIF 5A的毒性功能增加，破坏细胞内运输和神经元稳态。ALS相关的KIF 5A突变改变了C末端，其影响尚未阐明。在这里，Baron等人发现这些突变损害KIF 5A自身抑制，导致过度活跃的驱动蛋白，其显示改变的蛋白质功能和异常的细胞相互作用。这些观察结果揭示了导致ALS的机制。
Understandingthepathogenicmechanismsofdiseasemutationsiscriticaltoadvancingtreatments.ALS-associated mutations in the gene encoding the microtubule motorKIF5A result in skipping of exon 27 (KIF5AΔExon27) and the encoding of a protein with a novel 39 amino acid residue C-terminal sequence. Here, we report that expression of ALS-linked mutant KIF5A results in dysregulated motor activity, cellular mislocalization, altered axonal transport, and decreased neuronal survival. Single-molecule analysis revealed that the altered C terminus of mutant KIF5A results in a constitutively active state. Furthermore, mutant KIF5A possesses altered protein and RNA interactions and its expression results in altered gene expression/splicing. Taken together, our data support the hypothesis that causative ALS mutations result in a toxic gain of function in the intracellular motor KIF5A that disrupts intracellular trafficking and neuronal homeostasis. ALS-associated KIF5A mutations alter the C terminus, the effect of which had yet to be elucidated. Here, Baron et al. discover that these mutations impair KIF5A autoinhibition resulting in a hyperactive kinesin that displays altered protein function and aberrant cellular interactions. These observations shed light on the mechanisms contributing to ALS.
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影响因子：
15.1
作者：
Fallini C;Bassell GJ;Rossoll W
通讯作者：
Rossoll W
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
DOI：
10.1073/pnas.1202922109
发表时间：
2012-04-10
影响因子：
11.1
作者：
Bilican, Bilada;Serio, Andrea;Chandran, Siddharthan
通讯作者：
Chandran, Siddharthan
影响因子：
14.8
作者：
Barmada, Sami J.;Serio, Andrea;Arjun, Arpana;Bilican, Bilada;Daub, Aaron;Ando, D. Michael;Tsvetkov, Andrey;Pleiss, Michael;Li, Xingli;Peisach, Daniel;Shaw, Christopher;Chandran, Siddharthan;Finkbeiner, Steven
通讯作者：
Finkbeiner, Steven
影响因子：
16
作者：
Duran A;Amanchy R;Linares JF;Joshi J;Abu-Baker S;Porollo A;Hansen M;Moscat J;Diaz-Meco MT
通讯作者：
Diaz-Meco MT