Ubiquitylation is now recognized as comparable in importance to phosphorylation for regulating the activities of cellular proteins; but it is a much more complicated process, involving three enzymes and a sequence of at least four reactions. Three of these reactions are catalyzed by the first enzyme in the series, the E1 ubiquitin activating enzyme, which undergoes a remarkable sequence of structural rearrangements in the course of passing the small protein ubiquitin from one active site to the next, to be activated, thioesterified and handed off to the next enzyme in the series (the E2), for further modification and transfer to the target protein.
As so often with structural studies, homologous proteins from various species have been recruited to build a picture of the structural basis of the E1 mechanism, and the details of E1 structural acrobatics have been worked out by Brenda Schulman and colleagues from St. Jude Children’s Research Hospital, USA and by Christopher Lima and colleagues from Sloan-Kettering Institute, USA through a collage of pictures largely derived from two different E1s juggling with two different ubiquitin-related small proteins (SUMO and NEDD8). These are described, with exemplary schematic diagrams, in a recent review in BMC Biology by Sonja Lorenz and colleagues Aaron Cantor, Michael Rape and John Kuriyan from the University of California, Berkeley, USA, who also discuss the structural flexibility required for transfer to the target by E3 enzymes, and the exploitation of this flexibility in the regulation of ubiquitin signalling.
The minutiae of structure and mechanism, however, no matter how elegant, do not always lend themselves to lively and engaging prose, and in response to the comment of a referee to this effect, Lorenz and colleagues have summarized the macromolecular juggling sequence as the E1 passes its substrate from one catalytic site to the next in a video – with the careful disclaimer that the transitions between the different states captured by the crystal structures are of course hypothetical. The domains light up in color as each comes into play, and the whole thing is set to the score of ‘The juggler’ by Ernst Toch, modified and performed on the piano by first author Sonja Lorenz, and culminating in a triumphant chord as the E2 enzyme docks into its binding site at the end of the sequence.