英国布里斯托大学Peter J. Cullen等研究人员合作揭示Ritscher-Schinzel综合征相关内体指挥官复合物的结构。该项研究成果发表在2023年5月11日出版的《细胞》杂志上。

结合X射线晶体学、电子低温显微镜和计算预测，研究人员组装了一个完整的指挥官结构模型。Retriever与内体Retromer复合体有远距离关系，但有独特的特征，防止共享的VPS29亚单位与Retromer相关因子相互作用。COMMD蛋白形成一个独特的异源十聚环，通过与CCDC22和CCDC93的广泛相互作用而稳定。这些蛋白采用盘绕结构，连接CCC和Retriever组合，并招募第16个亚单位DENND10，从而形成完整的指挥官复合物。该结构允许绘制致病突变图谱，并揭示了这个演化保守贩运机器的功能所需的分子特征。

据了解，指挥官复合物是不同跨膜载体的内体回收所需的，其在Ritscher-Schinzel综合征中发生了突变。它由两个亚组合组成： Retriever由VPS35L、VPS26C和VPS29组成；CCC复合物包含12个亚单位： COMMD1-COMMD10和含卷曲结构域（CCDC）的蛋白质CCDC22和CCDC93。

附：英文原文

Title: Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome

Author: Michael D. Healy, Kerrie E. McNally, Rebeka Butkovi, Molly Chilton, Kohji Kato, Joanna Sacharz, Calum McConville, Edmund R.R. Moody, Shrestha Shaw, Vicente J. Planelles-Herrero, Sathish K.N. Yadav, Jennifer Ross, Ufuk Borucu, Catherine S. Palmer, Kai-En Chen, Tristan I. Croll, Ryan J. Hall, Nikeisha J. Caruana, Rajesh Ghai, Thi H.D. Nguyen, Kate J. Heesom, Shinji Saitoh, Imre Berger, Christiane Schaffitzel, Tom A. Williams, David A. Stroud, Emmanuel Derivery, Brett M. Collins, Peter J. Cullen

Issue&Volume: 2023/05/11

Abstract: The Commander complex is required for endosomal recycling of diverse transmembrane cargos and is mutated in Ritscher-Schinzel syndrome. It comprises two sub-assemblies: Retriever composed of VPS35L, VPS26C, and VPS29; and the CCC complex which contains twelve subunits: COMMD1-COMMD10 and the coiled-coil domain-containing (CCDC) proteins CCDC22 and CCDC93. Combining X-ray crystallography, electron cryomicroscopy, and in silico predictions, we have assembled a complete structural model of Commander. Retriever is distantly related to the endosomal Retromer complex but has unique features preventing the shared VPS29 subunit from interacting with Retromer-associated factors. The COMMD proteins form a distinctive hetero-decameric ring stabilized by extensive interactions with CCDC22 and CCDC93. These adopt a coiled-coil structure that connects the CCC and Retriever assemblies and recruits a 16th subunit, DENND10, to form the complete Commander complex. The structure allows mapping of disease-causing mutations and reveals the molecular features required for the function of this evolutionarily conserved trafficking machinery.

DOI: 10.1016/j.cell.2023.04.003

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00398-7