Tom1 Modulates Binding of Tollip to Phosphatidylinositol 3-Phosphate via a Coupled Folding and Binding Mechanism

作者：Xiao Shuyan; Brannon Mary K; Zhao Xiaolin; Fread Kristen I; Ellena Jeffrey F; Bushweller John H; Finkielstein Carla V; Armstrong Geoffrey S; Capelluto Daniel G S^*

来源：Structure, 2015, 23(10): 1910-1920.

DOI：10.1016/j.str.2015.07.017

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 andCUE 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.

• 出版日期2015-10-6
• 单位美国弗吉尼亚理工大学(Virginia Tech)