Abstract
SummaryClient protein recruitment to the Hsp90 system depends on cochaperones that bind the client and Hsp90 simultaneously and facilitate their interaction. Hsp90 involvement in the assembly of snoRNPs, RNA polymerases, PI3-kinase-like kinases, and chromatin remodeling complexes depends on the TTT (Tel2-Tti1-Tti2), and R2TP complexes—consisting of the AAA-ATPases Rvb1 and Rvb2, Tah1 (Spagh/RPAP3 in metazoa), and Pih1 (Pih1D1 in humans)—that together provide the connection to Hsp90. The biochemistry underlying R2TP function is still poorly understood. Pih1 in particular, at the heart of the complex, has not been described at a structural level, nor have the multiple protein-protein interactions it mediates been characterized. Here we present a structural and biochemical analysis of Hsp90-Tah1-Pih1, Hsp90-Spagh, and Pih1D1-Tel2 complexes that reveal a domain in Pih1D1 specific for binding CK2 phosphorylation sites, and together define the structural basis by which the R2TP complex connects the Hsp90 chaperone system to the TTT complex.
Highlights
The R2TP complex is implicated in the stabilization and assembly of an eclectic set of proteins and macromolecular complexes (Te et al, 2007; Zhao et al, 2005)
Client protein recruitment to the Hsp90 system depends on cochaperones that bind the client and Hsp90 simultaneously and facilitate their interaction
Hsp90 involvement in the assembly of small nucleolar ribonucleoproteins (snoRNPs), RNA polymerases, PI3-kinase-like kinases, and chromatin remodeling complexes depends on the TTT (Tel2Tti1-Tti2), and R2TP complexes—consisting of the AAA-ATPases Rvb1 and Rvb2, Tah1 (Spagh/RPAP3 in metazoa), and Pih1 (Pih1D1 in humans)—that together provide the connection to Hsp90
Summary
The R2TP complex is implicated in the stabilization and assembly of an eclectic set of proteins and macromolecular complexes (Te et al, 2007; Zhao et al, 2005) These include RNA polymerase 2 (Boulon et al, 2010), small nucleolar ribonucleoproteins (snoRNPs; Kakihara and Houry, 2012), and phosphatidylinositol-3-kinase-like kinases (PIKKs) such as mTOR and SMG1 (Horejsı et al, 2010; Takai et al, 2010). Pih is the multipoint scaffold of the R2TP complex, coupling the Rvb1-Rvb hetero-dodecamer, the Hsp chaperone machinery (via Tah in yeast or Spagh/RPAP3 in metazoa), and the TTT (Tel2-Tti1-Tti2) complex implicated in activation and stabilization of PIKKs (Hurov et al, 2010; Kakihara and Houry, 2012). The interaction of Pih and Hsp is mediated by Spagh/RPAP3, a much larger protein containing tandem TPR domains as well as additional domains of unknown function
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