Gallon Matthew, Clairfeuille Thomas, Steinberg Florian, Mas Caroline, Ghai Rajesh, Sessions Richard B, Teasdale Rohan D, Collins Brett M, Cullen Peter J
The Henry Wellcome Integrated Signalling Laboratories, School of Biochemistry, University of Bristol, Bristol BS8 1TD, United Kingdom;
Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072, Australia; and.
Proc Natl Acad Sci U S A. 2014 Sep 2;111(35):E3604-13. doi: 10.1073/pnas.1410552111. Epub 2014 Aug 18.
The sorting nexin 27 (SNX27)-retromer complex is a major regulator of endosome-to-plasma membrane recycling of transmembrane cargos that contain a PSD95, Dlg1, zo-1 (PDZ)-binding motif. Here we describe the core interaction in SNX27-retromer assembly and its functional relevance for cargo sorting. Crystal structures and NMR experiments reveal that an exposed β-hairpin in the SNX27 PDZ domain engages a groove in the arrestin-like structure of the vacuolar protein sorting 26A (VPS26A) retromer subunit. The structure establishes how the SNX27 PDZ domain simultaneously binds PDZ-binding motifs and retromer-associated VPS26. Importantly, VPS26A binding increases the affinity of the SNX27 PDZ domain for PDZ- binding motifs by an order of magnitude, revealing cooperativity in cargo selection. With disruption of SNX27 and retromer function linked to synaptic dysfunction and neurodegenerative disease, our work provides the first step, to our knowledge, in the molecular description of this important sorting complex, and more broadly describes a unique interaction between a PDZ domain and an arrestin-like fold.
分选连接蛋白27（SNX27）-逆转录复合物是含有PSD95、Dlg1、zo-1（PDZ）结合基序的跨膜货物从内体到质膜循环的主要调节因子。在此，我们描述了SNX27-逆转录复合物组装中的核心相互作用及其对货物分选的功能相关性。晶体结构和核磁共振实验表明，SNX27 PDZ结构域中一个暴露的β-发夹与液泡蛋白分选26A（VPS26A）逆转录亚基的抑制蛋白样结构中的一个凹槽结合。该结构确定了SNX27 PDZ结构域如何同时结合PDZ结合基序和逆转录相关的VPS26。重要的是，VPS26A结合使SNX27 PDZ结构域对PDZ结合基序的亲和力提高了一个数量级，揭示了货物选择中的协同作用。由于SNX27和逆转录复合物功能的破坏与突触功能障碍和神经退行性疾病有关，据我们所知，我们的工作为这一重要分选复合物的分子描述迈出了第一步，更广泛地描述了PDZ结构域与抑制蛋白样折叠之间的独特相互作用。
