Autism-associated SHANK3 missense point mutations impact conformational fluctuations and protein turnover at synapses.
Autism-associated SHANK3 missense point mutations impact conformational fluctuations and protein turnover at synapses.
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DOI：
10.7554/elife.66165
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发表时间：
2021-05-04
期刊：
影响因子：
7.7
通讯作者：
Mikhaylova M
中科院分区：
文献类型：
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作者：
Bucher M;Niebling S;Han Y;Molodenskiy D;Hassani Nia F;Kreienkamp HJ;Svergun D;Kim E;Kostyukova AS;Kreutz MR;Mikhaylova M
SH 3-和锚蛋白重复序列（SHANK）蛋白家族的成员被认为是突触后神经元突触密度的主要支架。典型SHANK 3亚型内的几个错义突变已被提出为自闭症谱系障碍（ASD）发展的病因。然而，有一个令人惊讶的缺乏数据连接错义突变引起的蛋白质结构和动态的变化，发生ASD相关的突触表型。在这项原理验证研究中，我们专注于两个ASD相关的点突变，两者都位于SHANK 3的同一结构域内，并证明这两种突变蛋白确实显示出二级和三级结构的明显变化以及更高的构象波动。大鼠原代海马神经元局部和远端结构紊乱导致突触靶向改变和突触部位蛋白质周转的变化。
Members of the SH3- and ankyrin repeat (SHANK) protein family are considered as master scaffolds of the postsynaptic density of glutamatergic synapses. Several missense mutations within the canonical SHANK3 isoform have been proposed as causative for the development of autism spectrum disorders (ASDs). However, there is a surprising paucity of data linking missense mutation-induced changes in protein structure and dynamics to the occurrence of ASD-related synaptic phenotypes. In this proof-of-principle study, we focus on two ASD-associated point mutations, both located within the same domain of SHANK3 and demonstrate that both mutant proteins indeed show distinct changes in secondary and tertiary structure as well as higher conformational fluctuations. Local and distal structural disturbances result in altered synaptic targeting and changes of protein turnover at synaptic sites in rat primary hippocampal neurons.