SNX27-FERM-SNX1 complex structure rationalizes divergent trafficking pathways by SNX17 and SNX27
SNX27-FERM-SNX1 complex structure rationalizes divergent trafficking pathways by SNX17 and SNX27
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SNX27-FERM-SNX1 复杂结构合理化了 SNX17 和 SNX27 不同的贩运途径
DOI：
10.1073/pnas.2105510118
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发表时间：
2021-09-07
影响因子：
11.1
通讯作者：
Jia, Da
中科院分区：
文献类型：
--
作者：
Yong, Xin;Zhao, Lin;Jia, Da
意义分类连接蛋白对于内体运输和信号传导至关重要。SNX 17和SNX 27是两种SNX蛋白，在结构域结构上具有高度相似性，包括共同的FERM结构域;然而，它们介导不同的内吞再循环途径。我们现在通过证明SNX 17和SNX 27的FERM结构域具有不同的功能来解决这个谜团。SNX 17的FERM结构域识别NPxY/NxxY基序，而SNX 27中的相同结构域结合SNX 1/2的N末端内的新型“DLF”基序。SNX 27和SNX 1/2之间的相互作用不仅有助于有效回收多种货物，而且还促进SNX 27的内体募集。我们进一步证明了SNX 27-SNX 1/2相互作用对斑马鱼神经元生长和大脑发育至关重要。决定内化膜蛋白的回收与降解命运的分子事件仍然知之甚少。SNX-FERM家族的三个成员中的两个，SNX 17和SNX 31，利用它们的FERM结构域来介导具有NPxY/NxxY基序的货物蛋白的内吞运输。相比之下，SNX 27不回收含有NPxY/NxxY的货物，而是通过其PDZ结构域回收含有PDZ结合基序的货物。FERM结构域结合的这种差异的潜在机制知之甚少。在这里，我们报告SNX 27的FERM结构域在功能上与SNX 17不同，并且与位于SNX 1/2的N末端内的新DLF基序相互作用，而不是货物蛋白中的NPxY/NxxY基序。SNX 27-FERM-SNX 1复合物结构揭示SNX 1的DLF基序结合到SNX 27表面上由带正电荷的残基包围的疏水洞穴。SNX 27和SNX 1/2之间的相互作用对于SNX 27有效募集到内体和多种货物的内吞再循环至关重要。最后，我们表明SNX 27和SNX 1/2之间的相互作用对斑马鱼的大脑发育至关重要。总之，我们的研究解决了该领域长期存在的难题，并表明SNX 27和SNX 17通过根本不同的机制介导内吞再循环。
Significance The sorting nexin proteins are critical for endosomal trafficking and signaling. SNX17 and SNX27 are two SNX proteins displaying high similarity in domain structure, including a common FERM domain; however, they mediate distinct endocytic recycling pathways. We now solve this mystery by demonstrating that the FERM domains of SNX17 and SNX27 have different functions. Whereas the FERM domain of SNX17 recognizes the NPxY/NxxY motif, the same domain in SNX27 binds to a novel “DLF” motif within the N termini of SNX1/2. The interaction between SNX27 and SNX1/2 not only helps efficient retrieval of multiple cargoes but also promotes endosomal recruitment of SNX27. We further demonstrate that the SNX27–SNX1/2 interaction is crucial to neuronal growth and brain development in zebrafish. The molecular events that determine the recycling versus degradation fates of internalized membrane proteins remain poorly understood. Two of the three members of the SNX-FERM family, SNX17 and SNX31, utilize their FERM domain to mediate endocytic trafficking of cargo proteins harboring the NPxY/NxxY motif. In contrast, SNX27 does not recycle NPxY/NxxY-containing cargo but instead recycles cargo containing PDZ-binding motifs via its PDZ domain. The underlying mechanism governing this divergence in FERM domain binding is poorly understood. Here, we report that the FERM domain of SNX27 is functionally distinct from SNX17 and interacts with a novel DLF motif localized within the N terminus of SNX1/2 instead of the NPxY/NxxY motif in cargo proteins. The SNX27-FERM-SNX1 complex structure reveals that the DLF motif of SNX1 binds to a hydrophobic cave surrounded by positively charged residues on the surface of SNX27. The interaction between SNX27 and SNX1/2 is critical for efficient SNX27 recruitment to endosomes and endocytic recycling of multiple cargoes. Finally, we show that the interaction between SNX27 and SNX1/2 is critical for brain development in zebrafish. Altogether, our study solves a long-standing puzzle in the field and suggests that SNX27 and SNX17 mediate endocytic recycling through fundamentally distinct mechanisms.