The ‘Complex World’ of the Hsp90 Co-chaperone R2TP

The Hsp90 co-chaperone R2TP consists of the AAA+ ATPases, RUVBL1 (Rvb1p in yeast) and RUVBL2 (Rvb2 in yeast), which together make up a heterohexameric ring, in complex with PIH1D1 (Pih1p in yeast) and RPAP3 (Tah1p in yeast). R2TP is involved in the activation of client proteins, such as phosphatidylinositol 3 kinase-related kinases, including mTORC1, ATM, DNA-PK, SMG and ATR/ATRIP, or in the assembly of protein complexes including those of RNA polymerase and snoRNPs, amongst others. In other cases, the role of the TP component (RPAP3-PIH1D1) of R2TP, and consequently Hsp90, is controversial. None-the-less, the extensive role of RUVBL1-RUVBL2 complex in cells, either with or without Hsp90, means that dysfunction of these AAA+ ATPases, Hsp90 or components of the complexes they assemble leads to diseases such as cancer, ciliary dyskinesia and in the case of defects in ATM to ataxia telangiectasia-like syndrome. Recent advances in determining the structure of the R2TP complex has led to an increased understanding of the assembly and function of the R2TP complex. In this review we discuss the current structural advances in determining the architecture of the R2TP complex and the advances made in understanding its active state.