Lucas María, Gershlick David C, Vidaurrazaga Ander, Rojas Adriana L, Bonifacino Juan S, Hierro Aitor
Structural Biology Unit, CIC bioGUNE, Bizkaia Technology Park, 48160 Derio, Spain.
Cell Biology and Neurobiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Cell. 2016 Dec 1;167(6):1623-1635.e14. doi: 10.1016/j.cell.2016.10.056. Epub 2016 Nov 23.
Retromer is a multi-protein complex that recycles transmembrane cargo from endosomes to the trans-Golgi network and the plasma membrane. Defects in retromer impair various cellular processes and underlie some forms of Alzheimer's disease and Parkinson's disease. Although retromer was discovered over 15 years ago, the mechanisms for cargo recognition and recruitment to endosomes have remained elusive. Here, we present an X-ray crystallographic analysis of a four-component complex comprising the VPS26 and VPS35 subunits of retromer, the sorting nexin SNX3, and a recycling signal from the divalent cation transporter DMT1-II. This analysis identifies a binding site for canonical recycling signals at the interface between VPS26 and SNX3. In addition, the structure highlights a network of cooperative interactions among the VPS subunits, SNX3, and cargo that couple signal-recognition to membrane recruitment.
回收体是一种多蛋白复合物，可将跨膜货物从内体循环至反式高尔基体网络和质膜。回收体缺陷会损害各种细胞过程，并成为某些形式的阿尔茨海默病和帕金森病的病因。尽管回收体在15多年前就已被发现，但其货物识别和向内体募集的机制仍不清楚。在这里，我们展示了一个四组分复合物的X射线晶体学分析，该复合物由回收体的VPS26和VPS35亚基、分选连接蛋白SNX3以及二价阳离子转运蛋白DMT1-II的一个循环信号组成。该分析确定了在VPS26和SNX3之间的界面处存在一个典型循环信号的结合位点。此外，该结构突出了VPS亚基、SNX3和货物之间的协同相互作用网络，这些相互作用将信号识别与膜募集联系起来。
