Structure and Membrane Binding Properties of the Endosomal Tetratricopeptide Repeat (TPR) Domain-containing Sorting Nexins SNX20 and SNX21
Structure and Membrane Binding Properties of the Endosomal Tetratricopeptide Repeat (TPR) Domain-containing Sorting Nexins SNX20 and SNX21
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DOI：
10.1074/jbc.m115.650598
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发表时间：
2015-06-05
影响因子：
4.8
通讯作者：
Collins, Brett M.
中科院分区：
文献类型：
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作者：
Clairfeuille, Thomas;Norwood, Suzanne J.;Collins, Brett M.
排序连接素(SNX)协调膜转运和信号传递，这是蛋白质在内体网络中正确分布所必需的。它们的Phox同源(Px)结构域作为磷脂酰肌醇(PI)识别模块，针对特定的内细胞膜结构域。SNX蛋白的模块化赋予了广泛的功能，从信号到膜变形和货物结合，许多SNX是内体动力学的重要调节器，参与了无数的生理和病理过程，如神经退行性疾病、癌症和炎症。在这里，我们研究了特征不佳的SNX20及其类似物SNX21，它包含一个N端的PX结构域和一个C端的未知功能的PX相关B(PXB)结构域。这两种蛋白具有相似的PI结合特性，并通过它们的Px结构域被招募到早期的内体隔室。SNX21 PXB结构域的晶体结构显示了一个四肽重复(TPR)折叠，这是一个通常与短肽基序结合的模块，具有三个TPRα-螺旋重复。然而，C-末端封顶螺旋采用了一种非常不寻常和潜在的自抑制拓扑。SNX20和SNX21的SAXS溶液结构表明，这些蛋白质采用致密的球状结构，膜相互作用分析表明存在重叠的PI结合部位，可能调节它们在细胞内的定位。这项研究首次对这个特征不佳的SNX蛋白亚家族进行了结构分析，强调了它可能作为内体相关支架的作用。
Sorting nexins (SNX) orchestrate membrane trafficking and signaling events required for the proper distribution of proteins within the endosomal network. Their phox homology (PX) domain acts as a phosphoinositide (PI) recognition module that targets them to specific endocytic membrane domains. The modularity of SNX proteins confers a wide variety of functions from signaling to membrane deformation and cargo binding, and many SNXs are crucial modulators of endosome dynamics and are involved in a myriad of physiological and pathological processes such as neurodegenerative diseases, cancer, and inflammation. Here, we have studied the poorly characterized SNX20 and its paralogue SNX21, which contain an N-terminal PX domain and a C-terminal PX-associated B (PXB) domain of unknown function. The two proteins share similar PI-binding properties and are recruited to early endosomal compartments by their PX domain. The crystal structure of the SNX21 PXB domain reveals a tetratricopeptide repeat (TPR)-fold, a module that typically binds short peptide motifs, with three TPR alpha-helical repeats. However, the C-terminal capping helix adopts a highly unusual and potentially self-inhibitory topology. SAXS solution structures of SNX20 and SNX21 show that these proteins adopt a compact globular architecture, and membrane interaction analyses indicate the presence of overlapping PI-binding sites that may regulate their intracellular localization. This study provides the first structural analysis of this poorly characterized subfamily of SNX proteins, highlighting a likely role as endosome-associated scaffolds.