Fig. 5.

Putative model of ataxin-3 function. Several functional groups are arranged in a linear fashion in ataxin-3. The Ub-binding site in the JD is followed in order by the catalytic site, the tandem UIMs, the polyQ stretch, and the variable C terminus that may contain a putative UIM. The tandem UIMs may recruit a polyubiquitinated substrate and present it to the JD. The JD holds a distal Ub in a tetrahedral intermediate state before releasing it after catalytic cleavage. The model implies that optimal substrates of ataxin-3 should have a minimum polyubiquitin chain length to allow engagement of both the second UIMs and the JD in Ub binding. Thus, the model is consistent with a role of ataxin-3 as a polyubiquitin-editing enzyme. The dotted lines connecting Ubs indicate the potential variable length of the polyubiquitin chain. The sequence around the polyQ stretch is responsible for the binding of ataxin-3 to VCP/p97, which may target ataxin-3, to function in one or more VCP/p97 pathways and/or directly mediate the regulation of the deubiquitinating activity of ataxin-3 by VCP/p97.