Targeting of proteins into peroxisomes

过氧体是所有真核细胞中必不可少的亚细胞室，与脂类代谢密切相关。在多个模型系统中的工作已经发现了至少32个编码过氧化物素的PEX基因，这些基因在过氧化物体的生物发生、形态发生(大小、体积和数量)和遗传中发挥作用。然而，尽管对所涉及的蛋白质有如此丰富的知识，但大多数过氧化物素的生化功能和作用机制还知之甚少。过氧化体蛋白通过两个过氧化体靶向信号PTS1和PTS2靶向细胞器基质。PTS受体结合在它们的货物上，与进口体相互作用，这是一种过氧酶体-膜相关的Pex蛋白的复合体。负责过氧化体基质蛋白转位的重要分子由对接和环亚复合体组成。在基质蛋白输入周期中，受体-货物复合体从胞浆中穿梭，与进口体相互作用，在过氧化体基质中释放货物，然后受体在受体循环亚复合体的帮助下穿梭回到胞浆中。过氧酶体生物发生领域的主要悬而未决的问题与不寻常的过氧体转位蛋白的确切性质、功能和结构有关，该转位蛋白不同于与其他亚细胞隔室相关的转运子，它运输折叠和寡聚的蛋白质(目标1)。双重基质蛋白输入途径的演变，以及从过氧化体释放货物和受体回收的步骤。涉及Pex8的功能，对于理解进口周期至关重要(目标2)。最近，内质网(ER)明显参与了过氧化体的形态发生，甚至生物发生，这就提出了一些重要的问题，即通过内质网对膜蛋白进行分类的机制以及这一途径在过氧化体生长和分裂中的功能作用(目标3)。最后，我们希望进一步探索关于过氧化物体生物发生、遗传和周转之间的串扰的有趣的新线索(目标4)。我们相信，我们在回答这些严重影响人类健康和疾病的根本性重要细胞生物学问题方面具有得天独厚的优势。

The peroxisome, an essential subcellular compartment in all eukaryotic cells, is infimately involved in lipid metabolism. Work in multiple model systems has uncovered at least 32 PEX genes encoding peroxins, that play roles In peroxisome biogenesis, morphogenesis (size, volume and number), and inheritance. However, despite this wealth of knowledge regarding the proteins involved, the biochemical functions and mechanisms of action of most peroxins are pooriy understood. Peroxisomal proteins are targeted to the organelle matrix by two peroxisomal targeting signals, PTS1 and PTS2. PTS receptors bound to their cargo interact with the importomer, a complex of peroxisome-membrane-assoclated Pex proteins. The importomer, responsible for peroxisomal matrix protein translocation is comprised of the docking and RING subcomplexes. During the matrix protein import cycle, the receptor-cargo complexes shuttle from the cytosol, interact with the importomer, release cargo in the peroxisome matrix and the receptors then shuttle back to the cytosol, aided by a receptor-recycling subcomplex. Major unanswered questions in the peroxisome biogenesis field relate to the exact nature, function and structure of the unusual peroxisomal translocon which, unlike translocons associated with other subcellular compartments, transports folded and oligomeric proteins across (Aim 1). The evolution of dual matrix protein import pathways and the steps in cargo release and receptor recycling from peroxisomes. Involving the function of Pex8, are critical for an understanding of the import cycle (Aim 2). The recent emergence of a clear involvement of the endoplasmic reficulum (ER) in peroxisome morphogenesis, and even biogenesis, raises important quesfions about the machinery that sorts peroxisomal membrane proteins via the ER and the funcfional role of this pathway in peroxisome growth and division (Aim 3). Finally, we wish to further explore fascinating emerging clues regarding a crosstalk between peroxisome biogenesis, inheritance and turnover (Aim 4). We believe we are uniquely positioned to answer these fundamentally important cell biological quesfions that seriously impact human health and disease.