Figure 7. Proposed model of sequential events during the interaction between ataxin-3, VCP/p97 and hHR23A.

(i) Ataxin-3 interacts with a monomer of the VCP/p97 hexamer through its ²⁸²RKRR region, assembling in a complex capable of recognizing the ubiquitinated substrate. (ii) Ataxin-3 acts on the branched ubiquitin chains attached to the ubiquitinated protein, originating a clear and perceptible ubiquitin signal. (iii) Due to its K63-linkage preference, ataxin-3 leaves an all K48-linkage ubiquitin chain on the surface of the protein. (iv) The ubiquitin signal released by ataxin-3 is recognized by hHR23A and interpreted as a degradation signal. (v) hHR23A delivers the ubiquitinated protein to the proteasome for degradation.