eLife · 2015 · 65 citations · 47 references
Life SciencesBiochemistryMolecular BiologyMolecular RecognitionStructural BiochemistryStructural BiologyConformational SelectionLigand BindingProtein ConformationProtein DynamicsProtein StructureStructural Basis Of RecognitionConformational TransitionsE3 Ubiquitin Ligase Substrate RecognitionPoint Mutation EffectsProtein Quaternary DynamicsQuaternary Structure DynamicsStructural Basis Of SpecificityTarget RecognitionUbiquitin System
A polyubiquitin comprises multiple covalently linked ubiquitins and recognizes myriad targets. Free or bound to ligands, polyubiquitins are found in different arrangements of ubiquitin subunits. To understand the structural basis for polyubiquitin quaternary plasticity and to explore the target recognition mechanism, we characterize the conformational space of Lys63-linked diubiquitin (K63-Ub2). Refining against inter-subunit paramagnetic NMR data, we show that free K63-Ub2 exists as a dynamic ensemble comprising multiple closed and open quaternary states. The quaternary dynamics enables K63-Ub2 to be specifically recognized in a variety of signaling pathways. When binding to a target protein, one of the preexisting quaternary states is selected and stabilized. A point mutation that shifts the equilibrium between the different states modulates the binding affinities towards K63-Ub2 ligands. This conformational selection mechanism at the quaternary level may be used by polyubiquitins of different lengths and linkages for target recognition.
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RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO
Carsten Hoege, Boris Pfander, George‐Lucian Moldovan et al. · Nature · 2002 · 2.2K citations