Stress-induced phospho-ubiquitin formation causes parkin degradation

Lyudmila Kovalchuke; Eugene V. Mosharov; Oren A. Levy; Lloyd A. Greene

An important question that our work raises is how parkin binding to phospho-Ub following cellular stress leads to its loss. One possibility is that the conformational change in parkin that occurs upon binding phospho-Ub [45] [46] [47] , [81] , [115] makes it vulnerable to degradation. If this is the case, the conformational change must be specific to phospho-Ub binding and not to that induced by parkin phosphorylation, because we show that only phospho-Ub binding is important for parkin loss. Both events have been proposed to release parkin's Ubl domain from its interaction with the RING1 domain [45] [46] [47] , [81] , [116] , and both have also The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/484857 doi: bioRxiv preprint been shown to facilitate the access of E2 ubiquitin-conjugating enzymes to parkin's E2 binding site [46] , [74] . Accordingly, neither of these effects is likely to be the crucial conformational change involved in parkin degradation. Instead, a conformational change that may promote parkin loss is movement of the IBR domain away from the Ubl domain. This movement has, thus far, only been attributed to phospho-Ub binding [47] , [115] , [117] , [118] , raising it as a plausible candidate trigger for parkin loss. Alternatively, instead of inducing a critical conformational change, parkin's association with phospho-Ub may cause parkin loss by bringing it into proximity with proteins that promote its degradation.