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Targeting of proteins into peroxisomes

将蛋白质靶向过氧化物酶体

基本信息

批准号：
8460880
负责人：
Suresh Subramani
金额：
$ 56.67万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-05-10 至 2014-04-30
项目状态：
已结题

项目摘要

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.

过氧化物酶体是所有真核细胞中必不可少的亚细胞隔室，密切参与脂质代谢。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，这些基因在过氧化物酶体的生物发生、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丰富的知识，但大多数过氧化物的生化功能和作用机制尚不清楚。过氧化物酶体蛋白通过两个过氧化物酶体靶向信号PTS1和PTS2靶向细胞器基质。与其货物结合的PTS受体与进口蛋白相互作用，进口蛋白是一种过氧化物酶体-膜相关的Pex蛋白复合物。负责过氧化物酶体基质蛋白易位的进口蛋白由对接和环亚复合物组成。在基质蛋白输入周期中，受体-货物复合物从细胞质中穿梭，与输入物相互作用，在过氧化物酶体基质中释放货物，然后受体在受体回收亚复合物的帮助下穿梭回细胞质。过氧化物酶体生物发生领域的主要未解问题与不寻常的过氧化物酶体转座子的确切性质、功能和结构有关，它与与其他亚细胞区室相关的转座子不同，可以跨区域运输折叠蛋白和低聚蛋白（Aim 1）。双基质蛋白输入途径的演变及过氧化物酶体的货物释放和受体再循环的步骤。涉及到Pex8的功能，对于理解导入周期至关重要（目标2）。最近出现的内质再流（ER）明确参与过氧化物酶体形态发生甚至生物发生的研究，提出了关于通过内质再流对过氧化物酶体膜蛋白进行分类的机制以及该途径在过氧化物酶体生长和分裂中的功能作用的重要问题（Aim 3）。最后，我们希望进一步探索关于过氧化物酶体生物发生，遗传和周转之间串扰的迷人新线索（Aim 4）。我们相信，我们有独特的优势来回答这些严重影响人类健康和疾病的重要细胞生物学问题。