Two mutations G335D and Q343R within the amyloidogenic core region of TDP-43 influence its aggregation and inclusion formation.
Two mutations G335D and Q343R within the amyloidogenic core region of TDP-43 influence its aggregation and inclusion formation.
复制标题
TDP-43 淀粉样蛋白核心区域内的两个突变 G335D 和 Q343R 影响其聚集和包涵体形成
DOI：
10.1038/srep23928
复制
发表时间：
2016-03-31
影响因子：
4.6
通讯作者：
Hu HY
中科院分区：
文献类型：
--
作者：
Jiang LL;Zhao J;Yin XF;He WT;Yang H;Che MX;Hu HY
TDP-43是与TDP-43蛋白病相关的DNA/RNA结合蛋白。已经在柔性C-末端区域中鉴定了许多突变，其与疾病病理学有关。我们通过生化和光谱方法研究了TDP-43的淀粉样蛋白核心区（残基311-360）中的四个点突变。我们发现G335 D突变增强了TDP-43的聚集和内含物形成，并且TDP-35中的该突变体（35 kDa的C末端片段）夸大了内源性TDP-43对RNA加工的拮抗作用;而Q343 R则产生相反的作用。作为比较，M337 V和Q331 K对TDP-43或TDP-35的聚集和包裹体形成的影响非常小。核磁共振结构分析表明，G335 D突变体在核心区的两个α-螺旋之间形成了一个环状接头，促进了α-到-β的转变，而Q343 R则失去了第二个螺旋，从而导致了结构的转变。因此，TDP-43的淀粉样蛋白生成核心中的结构转化倾向决定了其聚集和内含物形成。本研究可能为TDP-43基因突变引起的蛋白质病提供分子机制。
TDP-43 is a DNA/RNA binding protein associated with TDP-43 proteinopathies. Many mutations have been identified in the flexible C-terminal region, which is implicated in the disease pathology. We investigated four point mutations in the amyloidogenic core region (residues 311–360) of TDP-43 by biochemical and spectroscopic methods. We found that the G335D mutation enhances the aggregation and inclusion formation of TDP-43 and this mutant in TDP-35 (the C-terminal fragment of 35 kDa) exaggerates the antagonist effect on RNA processing by endogenous TDP-43; whereas Q343R gives an opposite effect. As a comparison, M337V and Q331K have very little impact on the aggregation and inclusion formation of TDP-43 or TDP-35. NMR structural analysis showed that the G335D mutant in the core region forms a loop linker between the two α-helices and promotes α-to-β transition, but Q343R loses the second helix and consequently the structural transformation. Thus, the propensity of structural transformation in the amyloidogenic core of TDP-43 determines its aggregation and inclusion formation. This study may provide a molecular mechanism of the TDP-43 proteinopathies caused by genetic mutations.