Dietary flavonoid fisetin binds human SUMO1 and blocks sumoylation of p53

PloS One
Vaithish VelazhahanKathrin Schrick

Abstract

Flavonoids are plant-derived compounds that occur abundantly in fruits and vegetables and have been shown to possess potent anti-cancer, antioxidant, and anti-inflammatory properties. However, their direct targets and molecular mechanism of action are not well characterized, hampering exploitation of the beneficial properties of flavonoids for drug development. Small ubiquitin-related modifier 1 (SUMO1) is attached to target proteins as part of a post-translational modification system implicated in a myriad of cellular processes from nuclear trafficking to transcriptional regulation. Using a combination of surface plasmon resonance, differential scanning fluorimetry and fluorescence quenching studies, we provide evidence for direct binding of the dietary flavonoid fisetin to human SUMO1. Our NMR chemical shift perturbation analyses reveal that binding to fisetin involves four conserved amino acid residues (L65, F66, E67, M82) previously shown to be important for conjugation of SUMO1 to target proteins. In vitro sumoylation experiments indicate that fisetin blocks sumoylation of tumor suppressor p53, consistent with fisetin negatively affecting post-translational modification and thus the biological activity of p53. A series of ...Continue Reading

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Methods Mentioned

BETA
sumoylation
surface
differential scanning fluorimetry
electrophoresis
surface plasmon resonance
saturation binding
Fluorescence
thermal shift
NMR
size exclusion chromatography

Software Mentioned

NMRFAM
ESPript
- Sparky
ClustalW
PyMOL2
GraphPad Prism7

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