Dev Kumlesh K, van der Putten Herman, Sommer Bernd, Rovelli Giorgio
Novartis Pharma AG, Nervous System Research, Unit of Neurodegeneration, CH-4002 Basel, Switzerland.
Neuropharmacology. 2003 Jul;45(1):1-13. doi: 10.1016/s0028-3908(02)00337-4.
Parkin is an E3 ligase that plays an important role in the ubiquitin/proteosome pathway responsible for protein degradation events. Mutations in parkin result in a loss-of-function and lead to Parkinson's disease, a progressive neurological disorder of movement. Presumably, this occurs due to the toxic build-up of proteins that are no longer effectively cleared/degraded by the parkin-dependent ubiqutin/proteosome pathway. To date, three types of proteins have been shown to interact with parkin. Firstly, the E2 ubiquitin conjugating proteins called UbcH7 and UbcH8 interact with parkin. Secondly, putative substrates interacting with parkin include a synaptic vesicle associated GTPase named CDCrel-1; a G protein-coupled receptor named Pael; a novel from of alpha-synuclein; and an alpha-synuclein interacting protein synphilin-1. Thirdly and more recently, a PDZ domain containing scaffolding protein CASK/Lin2 has been shown to interact with the PDZ binding motif of parkin. A network of PDZ-interacting proteins has potential to form a complex web of molecules that surround parkin and regulate its subcellular localisation and function.
帕金蛋白是一种E3连接酶，在负责蛋白质降解过程的泛素/蛋白酶体途径中发挥重要作用。帕金蛋白的突变会导致功能丧失，并引发帕金森病，这是一种进行性运动神经障碍。据推测，这是由于蛋白质的毒性积累所致，这些蛋白质不再能被依赖帕金蛋白的泛素/蛋白酶体途径有效清除/降解。迄今为止，已发现三种类型的蛋白质与帕金蛋白相互作用。首先，名为UbcH7和UbcH8的E2泛素结合蛋白与帕金蛋白相互作用。其次，与帕金蛋白相互作用的假定底物包括一种名为CDCrel-1的突触小泡相关GTP酶；一种名为Pael的G蛋白偶联受体；一种新型的α-突触核蛋白；以及一种与α-突触核蛋白相互作用的蛋白——突触核蛋白相互作用蛋白1。第三，也是最近发现的，一种含有PDZ结构域的支架蛋白CASK/Lin2已被证明与帕金蛋白的PDZ结合基序相互作用。一个由与PDZ相互作用的蛋白质组成的网络有可能形成一个围绕帕金蛋白的复杂分子网络，从而调节其亚细胞定位和功能。
