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

Nesprins是一种巨大的脊椎动物核膜的营养不良蛋白样蛋白（>800 kDa）。它们的n端包含一个能与肌动蛋白细胞骨架结合的-肌动蛋白型肌动蛋白结合域，而它们的c端包含一个能特异性靶向核膜的跨膜结构域。秀丽隐杆线虫核迁移与核锚定的遗传学研究然而，建立这些功能的机制仍然难以捉摸。我们实验室最近的证据表明，Nesprins与p150- glue和轻链1激酶直接相关。本提案的范围是揭示Nesprin介导的与微管运动蛋白和细胞骨架相互作用的分子细节，并研究它们在核生物学各个方面的功能重要性。为了实现这一目标，我们将使用生物化学、细胞生物学和遗传方法的结合。阐明Nesprins的功能及其关联可能有助于描述和解开基本的细胞生物学过程，从而为更好地理解层叠性人类疾病提供基础。

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.