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

Structure
Shuyan XiaoDaniel G S Capelluto

Abstract

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.

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Citations

Mar 16, 2016·Data in Brief·Shuyan XiaoDaniel G S Capelluto
Jun 9, 2016·Inflammatory Bowel Diseases·Christina BegkaMichel H Maillard
Oct 6, 2016·Biomolecular NMR Assignments·Jeffrey F EllenaDaniel G S Capelluto
Feb 6, 2017·Protein Science : a Publication of the Protein Society·Tuo-Xian TangDaniel G S Capelluto
Apr 21, 2020·The EMBO Journal·Thomas A RyanDavid A Tumbarello
May 23, 2017·Frontiers in Immunology·Elizabeth J A Kowalski, Liwu Li
Oct 2, 2019·Proceedings of the National Academy of Sciences of the United States of America·Alessandra Cadete MartiniFrank M LaFerla
Jul 3, 2019·NPJ Genomic Medicine·Salla KeskitaloMarkku Varjosalo
May 4, 2017·American Journal of Respiratory and Critical Care Medicine·Javeed A ShahThomas R Hawn
Jan 12, 2021·Frontiers in Cellular and Infection Microbiology·Ching-Yu LinIchiro Nakagawa
Mar 16, 2021·Frontiers in Cell and Developmental Biology·Tiffany G RoachDaniel G S Capelluto
Jul 16, 2021·Current Opinion in Immunology·Tarin M Bigley, Megan A Cooper

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