Model for atlastin-mediated membrane fusion. Hexagonal crystals of the cytosolic domain of human atlastin-1 in complex with GDP. Purified Yop1p induces tubule formation when reconstituted into proteoliposomes.

本实验室主要研究内质网等重要细胞器的形态与功能。内质网是一个广泛连续的膜网络,承担了蛋白合成、脂类合成和钙存储等重要功能。内质网的形态主要包括片 状和管状,然而这些不同形态的膜结构如何在同一膜系统内形成,我们还知之甚少。前期研究发现一组膜蛋白reticulons和DP1/Yop1p参与了管 状内质网的成形,这些膜蛋白只在管状内质网中存在,他们的过表达和敲除都会影响内质网的形态。我们纯化了两个成管膜蛋白,并发现他们在体外与脂肪重组后能 形成管状膜结构。我们最近又发现嵌膜GTP酶atlastin等参与了内质网管状网络的形成,这些蛋白的缺失或突变导致内质网分叉减少,也能引起遗传性痉 挛性截瘫。我们还通过结构解析等实验手段,剖析了atlastin介导膜融合的可能机制。总体来说,我们将采用细胞生物学,生物化学及结构生物学等多种方 法深入研究内质网塑形和重装的分子机制,内质网的形态与功能的关联,以及与内质网功能相关的疾病。

Biological membranes adopt different shapes, many of which are conserved amongst eukaryotes.  The morphological dynamics of the lipid bilayer have been shown to play important roles in many cellular processes, be it organelle biogenesis, endocytosis, or vesicular trafficking, and defects have been linked to many diseases. Endoplasmic reticulum (ER) is an organelle with extensive and continuous membrane network. How morphologically different ER domains are formed is not clear. Investigations of ER shaping and remodeling have led to the discovery of two groups of membrane proteins: the reticulons and DP1/Yop1p, proteins that are both necessary and sufficient for the generation of ER tubules; and a class of membrane-bound, dynamin-like GTPases, called atlastins, which appear to have a role in the fusion of ER membranes. Our recent structural and biochemical studies of atlastin provided first insight into the mechanism underlying ER fusion. We aim to use combined approaches to further investigate the mechanism and regulation of the tubular ER network formation. We are also interested in the functional significance of different ER morphologies, and their implication in various human diseases.