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Lisa Gentile


TUG-UBL1 (Tether Containing UBX Domain for GLUT-4 Ubiquitin Like 1) is a glucose transporter 4 (GLUT4) regulating protein which facilitates the release of GLUT4 transport vesicles when insulin stimulation is present. To understand the role of TUG-UBL1 in glucose metabolism, especially for type two diabetic patients for whom increases in insulin concentration do not correlate with increased glucose uptake, we explored the research question of whether TUG-UBL1 binds to insulin. Initially, models of full-length TUG-UBL1 (amino acids 1-473), the GLUT4 binding domain of TUG-UBL1 (amino acids 86-337), and the insulin heterodimer were built using PHYRE2. All of these structures were further refined with DeepRefiner, and then validated using MolProbity. Including all-atom contacts, full-length TUG-UBL1 scored in the 99th percentile, the GLUT4 binding domain of TUG-UBL1 scored in the 97th percentile, and the insulin heterodimer scored in the 97th percentile. Insulin binding to both the full-length TUG-UBL1 domain and the GLUT4 binding domain were then explored with HawkDock. In both cases, favorable binding energies were observed with predictions of GLUT4 binding region of TUG-UBL1 binding to insulin at -43.31 kcal/mol and full-length TUG-UBL1 binding to Insulin at -32.31 kcal/mol, with predictions favoring insulin binding to the GLUT4 binding domain. To support these computational findings, the GLUT4 binding domain of TUG-UBL1 is being over-expressed and purified for use in intrinsic tryptophan fluorescence binding studies with insulin. The finding of TUG-UBL1 binding to insulin are interesting in light of the potential implications the care type two diabetic patients as binding characterization could lead to further mechanistic understanding of insulin resistance and possible therapeutic development.

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