26S proteasome regulatory subunit ATPase 4 (human gene PSMC4; yeast ortholog Rpt4) (PSMC4 (Rpt4))

PSMC4 encodes Rpt4, one of six distinct AAA+ ATPase subunits (Rpt1–Rpt6) forming the heterohexameric motor in the 19S regulatory particle (RP, PA700) of the 26S proteasome. The 26S proteasome comprises a 20S core particle (CP) that houses proteolytic active sites and a 19S RP that recognizes polyubiquitylated substrates, removes ubiquitin (via Rpn11), unfolds substrates, opens the 20S α-ring gate, and translocates polypeptides into the CP. The AAA+ motor’s subunits, including Rpt4/PSMC4, bind and hydrolyze ATP in a coordinated, staircase-like cycle to power substrate unfolding/translocation; their C‑terminal tails engage α-ring pockets (HbYX-mediated interactions) to open the gate and couple mechanical work to proteolysis. Structural studies in yeast and human proteasomes have resolved distinct conformational states (e.g., s1–s4) and nucleotide occupancy patterns among Rpt subunits, highlighting specialized features such as ADP-bound Rpt6 and variable pore-loop positions that orchestrate substrate processing. As an essential component of the UPS, PSMC4 participates in regulating cell cycle, transcription, DNA replication, signaling, and stress responses; dysfunction or inhibition of the proteasome impacts cancer biology, neurodegeneration, infection, and immunity.

Other names

Proteasome 26S subunit, ATPase, 4Rpt426S proteasome AAA-ATPase subunit 4Regulatory particle triple-A ATPase subunit 419S regulatory particle ATPase subunit 4Proteasome subunit PSMC4

Proteasome inhibitors: reversible or irreversible inhibition of the 20S proteolytic active sites (chymotrypsin-like, etc.), leading to accumulation of ubiquitylated proteins and secondary inhibition of the 19S AAA+ ATPase-driven processing cycle that includes PSMC4. Experimental tool compounds and mechanistic insights indicate that ATP hydrolysis by the heterohexameric AAA+ ring (Rpt1–Rpt6 including Rpt4/PSMC4) drives substrate unfolding/translocation; modulation of nucleotide states alters conformational cycling and gate opening.