College of Veterinary Medical and Life Sciences, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.
Mol Psychiatry. 2018 May;23(5):1278-1286. doi: 10.1038/mp.2017.138. Epub 2017 Jul 20.
Disrupted in schizophrenia 1 (DISC1) is a multi-functional scaffolding protein that has been associated with neuropsychiatric disease. The role of DISC1 is to assemble protein complexes that promote neural development and signaling, hence tight control of the concentration of cellular DISC1 in neurons is vital to brain function. Using structural and biochemical techniques, we show for we believe the first time that not only is DISC1 turnover elicited by the ubiquitin proteasome system (UPS) but that it is orchestrated by the F-Box protein, FBXW7. We present the structure of FBXW7 bound to the DISC1 phosphodegron motif and exploit this information to prove that disruption of the FBXW7-DISC1 complex results in a stabilization of DISC1. This action can counteract DISC1 deficiencies observed in neural progenitor cells derived from induced pluripotent stem cells from schizophrenia patients with a DISC1 frameshift mutation. Thus manipulation of DISC1 levels via the UPS may provide a novel method to explore DISC1 function.
精神分裂症相关蛋白 1（DISC1）是一种多功能支架蛋白，与神经精神疾病有关。DISC1 的作用是组装促进神经发育和信号转导的蛋白复合物，因此，神经元中细胞 DISC1 的浓度的严格控制对大脑功能至关重要。我们使用结构和生化技术，首次表明不仅 DISC1 的周转率是由泛素蛋白酶体系统（UPS）引发的，而且它是由 F 框蛋白 FBXW7 协调的。我们展示了 FBXW7 与 DISC1 磷酸降解基序结合的结构，并利用这些信息证明了 FBXW7-DISC1 复合物的破坏导致 DISC1 的稳定。这种作用可以抵消来自精神分裂症患者诱导多能干细胞衍生的神经祖细胞中 DISC1 移码突变观察到的 DISC1 缺乏。因此，通过 UPS 对 DISC1 水平的操纵可能提供一种探索 DISC1 功能的新方法。
