RPAP3: Structural evolution, chaperone networks, and disease implications of a transcriptional Co-chaperone

The functional versatility of Hsp90 relies on its association with specialized co-chaperones that regulate client recruitment and maturation. Among these, the R2TP complex, comprising RUVBL1, RUVBL2, RPAP3 (Tah1 in yeast), and PIH1D1, acts as a conserved assembly factor essential for the biogenesis of large multiprotein machineries, including RNA polymerases, snoRNPs, PIKKs, and mTOR signaling complexes. RPAP3 functions as a central scaffold within the R2TP-Hsp90 system, linking Hsp90 and Hsp70 to the RUVBL1/2 ATPase core through its TPR domains and C-terminal interaction with PIH1D1. This modular organization enables RPAP3 to integrate chaperone-mediated folding with client delivery and complex assembly. Notably, dysregulation of RPAP3 has been implicated in oncogenic processes, highlighting its biomedical relevance. This review synthesizes current structural, functional, and evolutionary insights into RPAP3, focusing on its role within the R2TP-Hsp90 machinery and its emerging connections to human disease.