Fig. 6: Model for the coordination of proteasome conformational changes, deubiquitination and TXNL1 binding.

a, TXNL1 loosely interacts with Rpn2, Rpn10 and Rpn11 of the RS proteasome and tightly binds PS proteasomes during substrate unfolding and translocation through additional contacts of its C-terminal tail with Rpn11’s catalytic groove, allowing a potential codegradational reduction of oxidized substrates. b, The conformationally selective binding of TXNL1 prevents interference with deubiquitination during the turnover of ubiquitin-tagged substrates. After ubiquitin binding to a receptor and Rpn11 in the RS proteasome, the insertion of the substrate’s flexible initiation region into the ATPase motor induces the conformational switch to PSs and subsequent or simultaneous cleavage of the affinity-conferring ubiquitin chain by Rpn11. TXNL1 then binds with high affinity during substrate unfolding and translocation; however, lower TXNL1 affinity and the exclusion of its C-terminal tail from Rpn11 in the PS_Rpt2 state would allow a cotranslocational removal of any additional ubiquitin chains.