Nesprins, nuclear dystrophin-like integrators of the cyto- and nucleoskeleton

Nesprins是核膜的巨大脊椎动物肌营养不良蛋白样蛋白（>800 kDa）。而它们的N-末端含有一个能够与肌动蛋白细胞骨架结合的<$-辅肌动蛋白型肌动蛋白结合结构域，它们的C-末端含有一个单一的跨膜结构域，该结构域将蛋白特异性靶向核膜。遗传学研究C.线虫暗示Nesprins参与核迁移和核锚定;然而，建立这种功能的机制仍然是难以捉摸的。我们实验室最近的证据表明，Nesprins与p150-Glued和驱动蛋白轻链1直接相关。该提案的范围是解开奈普林介导的相互作用的微管马达蛋白和细胞骨架的分子细节，并研究其在核生物学的各个方面的功能的重要性。为了实现这一目标，我们将使用生物化学，细胞生物学和遗传学方法的组合。阐明Nesprins及其相关性的功能可能有助于描述和解开基本的细胞生物学过程，从而为更好地理解laminopathic人类疾病提供基础。

Nesprins are giant vertebrate dystrophin like proteins (>800 kDa) of the nuclear envelope. Whereas their N-terminus contains an ¿-actinin type actin binding domain enabling an association with the actin cytoskeleton, their C-terminus contains a single transmembrane domain which targets the protein specifically to the nuclear membrane. Genetic studies in C. elegans implicate Nesprins in nuclear migration and nuclear anchorage; the mechanism however by which such functions are established remains elusive. Recent evidence in our laboratory indicates that Nesprins associate directly with p150-Glued and kinesin light chain 1. The scopes of this proposal are to unravel the molecular details of Nesprin mediated interactions with microtubule motor proteins and the cytoskeleton and to study their functional importance in various aspects of nuclear biology. In order to accomplish this we will use a combination of biochemical, cell biological and genetic approaches. Elucidating the function of Nesprins and their associations may help to delineate and disentangle fundamental cell biological processes, providing thus a basis towards a better understanding of laminopathic human diseases.