A unique PDZ domain and arrestin-like fold interaction reveals mechanistic details of endocytic recycling by SNX27-retromer
A unique PDZ domain and arrestin-like fold interaction reveals mechanistic details of endocytic recycling by SNX27-retromer
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DOI：
10.1073/pnas.1410552111
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发表时间：
2014-09-02
影响因子：
11.1
通讯作者：
Cullen, Peter J.
中科院分区：
文献类型：
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作者：
Gallon, Matthew;Clairfeuille, Thomas;Cullen, Peter J.
分类连接蛋白27 (SNX27)-反转录复合物是内体到质膜的跨膜货物循环的主要调节剂，这些跨膜货物含有PSD95， Dlg1, zo-1 （PDZ）结合基序。在这里，我们描述了SNX27-retromer组装中的核心相互作用及其与货物分拣的功能相关性。晶体结构和核磁共振实验表明，SNX27 PDZ结构域暴露的β发夹在液泡蛋白分选26A （VPS26A）反转录亚基的抑制蛋白样结构中有一个凹槽。该结构确定了SNX27 PDZ结构域如何同时结合PDZ结合基序和逆转录物相关的VPS26。重要的是，VPS26A结合将SNX27 PDZ结构域与PDZ结合基序的亲和力提高了一个数量级，揭示了货物选择的协同性。SNX27的破坏和逆转录功能与突触功能障碍和神经退行性疾病有关，据我们所知，我们的工作为这种重要的分选复合物的分子描述提供了第一步，并更广泛地描述了PDZ结构域和抑制蛋白样折叠之间的独特相互作用。
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 beta-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.