title: Tom1 Modulates Binding of Tollip to Phosphatidylinositol 3-Phosphate via a Coupled Folding and Binding Mechanism.
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.
authors: Protein Signaling Domains Laboratory, Department of Biological Sciences, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, VA 24061, USA.
authors: Shuyan
authors: S
authors: Xiao
authors: Protein Signaling Domains Laboratory, Department of Biological Sciences, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, VA 24061, USA.
authors: Mary K
authors: MK
authors: Brannon
authors: Protein Signaling Domains Laboratory, Department of Biological Sciences, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, VA 24061, USA.
authors: Xiaolin
authors: X
authors: Zhao
authors: Protein Signaling Domains Laboratory, Department of Biological Sciences, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, VA 24061, USA.
authors: Kristen I
authors: KI
authors: Fread
authors: Department of Chemistry and Biochemistry, University of Virginia, Charlottesville, VA 22904, USA.
authors: Jeffrey F
authors: JF
authors: Ellena
authors: Department of Chemistry and Biochemistry, University of Virginia, Charlottesville, VA 22904, USA.
authors: John H
authors: JH
authors: Bushweller
authors: Integrated Cellular Responses Laboratory, Department of Biological Sciences, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, VA 24061, USA.
authors: Carla V
authors: CV
authors: Finkielstein
authors: Departments of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, CO 80309, USA.
authors: Geoffrey S
authors: GS
authors: Armstrong
authors: Protein Signaling Domains Laboratory, Department of Biological Sciences, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, VA 24061, USA. Electronic address: capellut@vt.edu.
authors: Daniel G S
authors: DGS
authors: Capelluto
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D011992:Endosomes / Q000737:chemistry* / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D018129:Phosphatidylinositol Phosphates / Q000737:chemistry* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D018129:Phosphatidylinositol Phosphates; D011506:Proteins; D011993:Recombinant Fusion Proteins; C410602:TOLLIP protein, human; C120296:TOM1 protein, human; D025801:Ubiquitin; C055525:phosphatidylinositol 3-phosphate; D046988:Proteasome Endopeptidase Complex