Fig. 1: TXNL1 interacts with the substrate-degrading human 26S proteasomes and coordinates the active-site zinc of Rpn11.

a, Density of TXNL1’s PITH domain bound to the human 26S proteasome in PS_Rpt5 with Rpt5 at the top of the AAA+ ATPase spiral staircase and engaged with a translocating peptide during degradation of FAT10–Eos substrate delivered by NUB1. TXNL1’s PITH domain and C-terminal tail are shown in orange, the DUB Rpn11 is shown in petrol, Rpn2 is shown in salmon, Rpn1 and Rpn10’s VWA domains are shown in tomato, the AAA+ ATPase hexamer is shown in alternating dark blue and cyan, lid subunits (except Rpn11) are shown in light gray and the 20S CP is shown in dark gray. b, Top: schematic of TXNL1’s domain organization. Bottom: AlphaFold model of full-length TXNL1. The N-terminal TRX domain is flexibly attached to the C-terminal PITH domain and, therefore, not resolved in our EM maps. c, Atomic model of PS_Rpt5 with bound TXNL1. Right: zoomed-in views depicting the interfaces of TXNL1 with Rpn2 and Rpn10, as well as the Rpt pore 1 loops forming a spiral staircase around the translocating substrate polypeptide. d, Left: density for the PITH domain and its C-terminal tail bound to Rpn11, with Rpn11’s Ins-1 region shown in purple. Right: zoomed-in view of TXNL1’s C-terminal tail, with hydrophobic residues (M275 and F278) pointing toward Rpn11’s catalytic groove and the C-terminal H289 coordinating the active-site Zn²⁺.