Targeting of proteins into peroxisomes

过氧化物酶体是真核细胞中一个重要的亚细胞区室，它与脂质代谢密切相关。在多个模型系统中的工作已经发现了至少32个编码过氧化物酶的PEX基因，其在过氧化物酶体生物发生、形态发生（大小、体积和数量）和遗传中发挥作用。然而，尽管关于所涉及的蛋白质的知识如此丰富，但大多数过氧化物的生化功能和作用机制却知之甚少。过氧化物酶体蛋白通过两种过氧化物酶体靶向信号PTS 1和PTS 2靶向细胞器基质。PTS受体结合到他们的货物相互作用的输入体，过氧化物酶体膜assoclated Pex蛋白的复合物。负责过氧化物酶体基质蛋白易位的输入体由对接和RING亚复合物组成。在基质蛋白输入循环期间，受体-货物复合物从胞质溶胶穿梭，与输入体相互作用，在过氧化物酶体基质中释放货物，然后受体在受体再循环亚复合物的帮助下穿梭回到胞质溶胶。在过氧化物酶体生物发生领域中的主要未回答的问题涉及不寻常的过氧化物酶体转座体的确切性质、功能和结构，与其他亚细胞隔室相关的转座体不同，转座体转运折叠的和寡聚的蛋白质（目的1）。双重基质蛋白输入途径的演变以及过氧化物酶体中货物释放和受体再循环的步骤。涉及Pex 8的功能，对于理解进口周期至关重要（目标2）。最近出现的一个明确的参与内质网（ER）在过氧化物酶体的形态发生，甚至生物发生，提出了重要的问题，通过ER分类过氧化物酶体膜蛋白的机制，以及该途径在过氧化物酶体的生长和分裂的功能作用（目的3）。最后，我们希望进一步探索有关过氧化物酶体生物发生，遗传和营业额之间的串扰的迷人的新线索（目的4）。我们相信，我们处于独特的地位，可以回答这些严重影响人类健康和疾病的根本重要的细胞生物学问题。

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.