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Abstract
The R2TP complex is a HSP90 co-chaperone, which consists of four subunits: PIH1D1, RPAP3, RUVBL1, and RUVBL2. It is involved in the assembly of large protein or protein–RNA complexes such as RNA polymerase, small nucleolar ribonucleoproteins (snoRNPs), phosphatidylinositol 3 kinase-related kinases (PIKKs), and their complexes. While RPAP3 has a HSP90 binding domain and the RUVBLs comprise ATPase activities important for R2TP functions, PIH1D1 contains a PIH-N domain that specifically recognizes phosphorylated substrates of the R2TP complex. In this review we provide an overview of the current knowledge of the R2TP complex with the focus on the recently identified structural and mechanistic features of the R2TP complex functions. We also discuss the way R2TP regulates cellular response to stress caused by low levels of nutrients or by DNA damage and its possible exploitation as a target for anti-cancer therapy.
Highlights
Heat shock protein 90 (HSP90) AND ITS CO-CHAPERONES Chaperones are proteins involved in protein folding and proteincomplex assembly or disassembly (Macario and Conway de Macario, 2005)
It is involved in the assembly of large number of multi-subunit complexes: (a) the small nucleolar ribonucleoproteins, which are essential for biogenesis of ribosomes, spliceosomes, and tRNAs (Zhao et al, 2008; McKeegan et al, 2009); (b) RNA polymerase II (Boulon et al, 2010) and (c) phosphatidylinositol 3-kinase-related kinases (PIKKs) and their complexes (Horejsi et al, 2010) that are involved in DNA damage signaling (ATM, ATR, DNA-PKcs), transcription regulation (TRRAP), nonsense mediated mRNA decay (SMG1), and nutrient signaling
TEL2 phosphorylated on serine 487 and 491 by Casein Kinse 2 (CK2) binds to the PIH-N domain present in PIH1D1 and mutation of both serines disrupts its interaction with R2TP complex, but does not affect the binding of PIKKs and HSP90 (Horejsi et al, 2010)
Summary
HSP90 AND ITS CO-CHAPERONES Chaperones are proteins involved in protein folding and proteincomplex assembly or disassembly (Macario and Conway de Macario, 2005). These data indicate that PIH-N domain recognizes and recruits specific substrates to the R2TP during assembly of PIKKs, snoRNPs and RNA polymerase II and possibly of other complexes.
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