新功能、新界面、新体验,扫描即可下载生物谷APP!
首页 » 生物研究 » Nat Commun:生物物理所在结节性硬化症研究方面取得进展

Nat Commun:生物物理所在结节性硬化症研究方面取得进展

来源:生物物理研究所 2013-07-18 08:57

中科院生物物理研究所龚为民组、娄继忠组和结构生物学海外团队华盛顿大学许文清教授实验室对结节性硬化症的研究取得重要进展,该成果于7月16日在线发表在Nature Communications杂志上,题为Crystal structure of the yeast TSC1 core domain and implications for tuberous sclerosis pathological mutations。

结节性硬化症(Tuberous Sclerosis Complex, TSC)是一种常染色体主导的多系统疾病,以良性肿瘤的发生为标志,通常影响大脑、肾脏、皮肤、心脏和肺等器官,常常造成神经性疾病,包括癫痫、智障和自闭症。该疾病的发生主要由编码TSC1和TSC2蛋白的基因突变导致,TSC1和TSC2蛋白能形成复合物控制下游的TOR信号通路从而调控细胞生长。

Crystal structure of the core domain of yTSC1

发表在Nature Communications上的工作主要对TSC1上的点突变诱发结节性硬化症的分子机制做了深入研究。酵母TSC1能被蛋白酶降解出稳定的N端结构域,该结构域被实验和生物信息学两方面的证据佐证,被命名为核心结构域。该核心结构域在溶液中以二聚体的形式存在,但存在高聚体化的倾向,晶体中可形成十聚的五元环结构。令人惊讶的是,与酵母TSC1核心结构域对应的人源TSC1部分包含了几乎所有已知致病性点突变。该项研究解析了酵母TSC1核心结构域的晶体结构并用其模拟了对应的人源TSC1的结构,结合已知点突变的致病性信息,揭示了几乎所有致病性TSC1突变都是由于突变破坏了蛋白N端结构域的折叠。这些发现对针对结节性硬化症的药物设计具有重要的指导意义。(生物谷 Bioon.com)

生物谷推荐的英文摘要

Nature Communications  doi:10.1038/ncomms3135

Crystal structure of the yeast TSC1 core domain and implications for tuberous sclerosis pathological mutations

Wei Sun,  Ye Julia Zhu,  Zhizhi Wang,  Qiang Zhong,  Feng Gao,  Jizhong Lou,  Weimin Gong  & Wenqing Xu

Tuberous sclerosis complex is a disease caused by mutations in two tumor-suppressor genes, TSC1 and TSC2. The TSC1 protein, also known as hamartin, has a critical role in controlling mTOR signalling. TSC1 does not bear apparent sequence homology with other proteins. Here we show that the N-terminal half of yeast TSC1 forms a protease-resistant domain, which is evolutionarily conserved. The crystal structure of this yeast TSC1 core domain shows that it contains a pseudo-HEAT repeat fold with its C-terminal end capped by a helical subdomain. This allows us to model the three-dimensional structure of the human TSC1 N-terminal domain (TSC1-NTD), which anchors essentially all pathogenic TSC1 missense mutations found in tuberous sclerosis patients. Interestingly, most pathogenic mutations map inside of the folded TSC1-NTD structure, whereas most non-pathogenic variants are on the structural surface. This indicates that the disruption of the TSC1-NTD globular structure is a major cause of tuberous sclerosis.

温馨提示:87%用户都在生物谷APP上阅读,扫描立刻下载! 天天精彩!


相关标签

最新会议 培训班 期刊库