Tom1 Modulates Binding of Tollip to Phosphatidylinositol 3-Phosphate via a Coupled Folding and Binding Mechanism.
Tom1 Modulates Binding of Tollip to Phosphatidylinositol 3-Phosphate via a Coupled Folding and Binding Mechanism.
复制标题
Tom1 通过耦合折叠和结合机制调节 Tollip 与磷脂酰肌醇 3-磷酸的结合。
DOI：
10.1016/j.str.2015.07.017
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Capelluto,DanielGS
中科院分区：
文献类型：
--
作者：
Xiao,Shuyan;Brannon,MaryK;Zhao,Xiaolin;Fread,KristenI;Ellena,JeffreyF;Bushweller,JohnH;Finkielstein,CarlaV;Armstrong,GeoffreyS;Capelluto,DanielGS
早期的内体是囊泡泛素化货物的第一个分拣站。Tollip通过其C2结构域与内体磷脂酰肌醇3-磷酸(PtdIns(3)P)结合，并通过其C2和CUE结构域与这些隔室中泛素化的货物结合。Tom1通过其GAT结构域，通过未知的机制与Tollip Tom1结合结构域(TBD)被招募到内体。核磁共振数据表明，Tollip TBD是一个自然展开的结构域，当通过高亲和力疏水接触与Tom1 GAT结合时，它在N端部分折叠。此外，这种结合通过额外靶向Tollip的C2结构域而取消了Tollip与PtdIns(3)P的结合。Tom1 GAT也能够在重叠的位置结合泛素和PtdIns(3)P，尽管有一定的亲和力。我们认为，与Tom1的结合有利于Tollip从内膜释放，使Tollip能够从事货物运输。
Early endosomes represent the first sorting station for vesicular ubiquitylated cargo. Tollip, through its C2 domain, associates with endosomal phosphatidylinositol 3-phosphate (PtdIns(3)P) and binds ubiquitylated cargo in these compartments via its C2 and CUE domains. Tom1, through its GAT domain, is recruited to endosomes by binding to the Tollip Tom1-binding domain (TBD) through an unknown mechanism. Nuclear magnetic resonance data revealed that Tollip TBD is a natively unfolded domain that partially folds at its N terminus when bound to Tom1 GAT through high-affinity hydrophobic contacts. Furthermore, this association abrogates binding of Tollip to PtdIns(3)P by additionally targeting its C2 domain. Tom1 GAT is also able to bind ubiquitin and PtdIns(3)P at overlapping sites, albeit with modest affinity. We propose that association with Tom1 favors the release of Tollip from endosomal membranes, allowing Tollip to commit to cargo trafficking.