Structure of the TELO2-TTI1-TTI2 complex and its function in TOR recruitment to the R2TP chaperone

Pal, Mohinder; Muñoz-Hernández, Hugo; Bjorklund, Dennis M.; Zhou, Lihong; Degliesposti, Gianluca; Skehel, J. Mark; Hesketh, Emma L.; Thompson, Rebecca; Pearl, Laurence H.; Llorca, Óscar; Prodromou, Chrisostomos

doi:10.1016/j.celrep.2021.109317

Cited by 23 publications

(37 citation statements)

References 46 publications

(112 reference statements)

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“…The R2TP complex has been shown to stabilize client proteins belonging to the phosphatidylinositol 3-kinase-related kinase (PIKK) family, such as mTOR, ATM, ATR, DNA-PKcs, and SMG-1, via interaction with the TTT complex (TELO2-TTI1-TTI2) (Cloutier et al, 2017;Horejsi et al, 2010;Kamano et al, 2013;Pal et al, 2021). R2TP is also involved in the assembly of the TSC complex (TSC1-TSC2-TBC1D7), a regulator of mTORC1, U5 snRNPs and L7Ae RNPs (Cloutier et al, 2017;Malinova et al, 2017;Mir et al, 2015), and RNA polymerase II (Boulon et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Assembly principles of the human R2TP chaperone complex reveal the presence of R2T and R2P complexes

et al. 2022

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Section: Introductionmentioning

confidence: 99%

Assembly principles of the human R2TP chaperone complex reveal the presence of R2T and R2P complexes

et al. 2022

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“…How R2TP deals with a diversity of clients is still not well understood, but it has been suggested that ‘adaptor’ proteins contribute to put together the chaperone with specific clients. This model is best characterized for the assembly of mTOR complexes where a TELO2-TTI1-TTI2 (TTT) complex serves to bring mTOR to R2TP ( 11 , 45 ). For U5 snRNP, both ZNHIT2 and ECD have been proposed to function as linker between PRPF8 and R2TP ( 3 , 4 , 20 , 26 ).…”

Section: Resultsmentioning

confidence: 99%

“…Some of these factors could function as adaptor proteins or scaffolds connecting specific clients to the chaperone, while others could perform other, yet unknown, regulatory functions specific to each client. For example, the TTT complex acts as a scaffold between R2TP and clients during the biogenesis of the kinases of the PIKK family, but it also regulates the ATP hydrolysis and some of the interactions taking place within the R2TP complex ( 11 ). Our results suggest that ZNHIT2 could be part of a larger complex containing other regulatory subunits together with PRPF8 and R2TP.…”

Section: Discussionmentioning

confidence: 99%

“…RUVBL1 and RUVBL2 are closely related AAA-ATPases that form an hexameric RUVBL1–RUVBL2 ring of alternating subunits. Both subunits contain a domain, known as domain II (DII), that protrudes from each subunit in the RUVBL1–RUVBL2 hexamer and which has been found to interact with several proteins ( 8 , 11 , 12 ). The ATPase activity of RUVBL1 and RUVBL2, which resides in the AAA+ ring, is needed for the functions of R2TP ( 13 ), but what is the exact role of ATP hydrolysis and how this is regulated is mostly unknown.…”

Section: Introductionmentioning

confidence: 99%

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CryoEM of RUVBL1–RUVBL2–ZNHIT2, a complex that interacts with pre-mRNA-processing-splicing factor 8

Serna

González-Corpas

Cabezudo

et al. 2021

Nucleic Acids Research

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Biogenesis of the U5 small nuclear ribonucleoprotein (snRNP) is an essential and highly regulated process. In particular, PRPF8, one of U5 snRNP main components, requires HSP90 working in concert with R2TP, a cochaperone complex containing RUVBL1 and RUVBL2 AAA-ATPases, and additional factors that are still poorly characterized. Here, we use biochemistry, interaction mapping, mass spectrometry and cryoEM to study the role of ZNHIT2 in the regulation of the R2TP chaperone during the biogenesis of PRPF8. ZNHIT2 forms a complex with R2TP which depends exclusively on the direct interaction of ZNHIT2 with the RUVBL1–RUVBL2 ATPases. The cryoEM analysis of this complex reveals that ZNHIT2 alters the conformation and nucleotide state of RUVBL1–RUVBL2, affecting its ATPase activity. We characterized the interactions between R2TP, PRPF8, ZNHIT2, ECD and AAR2 proteins. Interestingly, PRPF8 makes a direct interaction with R2TP and this complex can incorporate ZNHIT2 and other proteins involved in the biogenesis of PRPF8 such as ECD and AAR2. Together, these results show that ZNHIT2 participates in the assembly of the U5 snRNP as part of a network of contacts between assembly factors required for PRPF8 biogenesis and the R2TP-HSP90 chaperone, while concomitantly regulating the structure and nucleotide state of R2TP.

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“…Tti2, together with its binding partners, Tti1 and telomere maintenance 2 (Telo2) protein, form the Triple T (TTT) complex [ 60 ], which associates with a number of molecular chaperones, including Hsp90, Hsp70, Hsp40, and the R2TP/prefoldin-like complex [ 61 , 62 ]. Interaction of TTT with R2TP modifies ATPase activity of R2TP components, RUVBL1-RUVBL2 [ 63 , 64 ]. TTT binds to nascent peptides of PI3K-related protein kinases (PIKK) and delivers them to the R2TP chaperone, thereby acting as a scaffold adaptor and a critical regulator of PIKK abundance in mammalian and yeast cells [ 60 , 62 – 67 ].…”

Section: Discussionmentioning

confidence: 99%

Systems genetics in the rat HXB/BXH family identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose

et al. 2022

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Neurogenesis in the adult hippocampus contributes to learning and memory in the healthy brain but is dysregulated in metabolic and neurodegenerative diseases. The molecular relationships between neural stem cell activity, adult neurogenesis, and global metabolism are largely unknown. Here we applied unbiased systems genetics methods to quantify genetic covariation among adult neurogenesis and metabolic phenotypes in peripheral tissues of a genetically diverse family of rat strains, derived from a cross between the spontaneously hypertensive (SHR/OlaIpcv) strain and Brown Norway (BN-Lx/Cub). The HXB/BXH family is a very well established model to dissect genetic variants that modulate metabolic and cardiovascular diseases and we have accumulated deep phenome and transcriptome data in a FAIR-compliant resource for systematic and integrative analyses. Here we measured rates of precursor cell proliferation, survival of new neurons, and gene expression in the hippocampus of the entire HXB/BXH family, including both parents. These data were combined with published metabolic phenotypes to detect a neurometabolic quantitative trait locus (QTL) for serum glucose and neuronal survival on Chromosome 16: 62.1–66.3 Mb. We subsequently fine-mapped the key phenotype to a locus that includes the Telo2-interacting protein 2 gene (Tti2)—a chaperone that modulates the activity and stability of PIKK kinases. To verify the hypothesis that differences in neurogenesis and glucose levels are caused by a polymorphism in Tti2, we generated a targeted frameshift mutation on the SHR/OlaIpcv background. Heterozygous SHR-Tti2+/- mutants had lower rates of hippocampal neurogenesis and hallmarks of dysglycemia compared to wild-type littermates. Our findings highlight Tti2 as a causal genetic link between glucose metabolism and structural brain plasticity. In humans, more than 800 genomic variants are linked to TTI2 expression, seven of which have associations to protein and blood stem cell factor concentrations, blood pressure and frontotemporal dementia.

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Structure of the TELO2-TTI1-TTI2 complex and its function in TOR recruitment to the R2TP chaperone

Cited by 23 publications

References 46 publications

Assembly principles of the human R2TP chaperone complex reveal the presence of R2T and R2P complexes

Assembly principles of the human R2TP chaperone complex reveal the presence of R2T and R2P complexes

CryoEM of RUVBL1–RUVBL2–ZNHIT2, a complex that interacts with pre-mRNA-processing-splicing factor 8

Systems genetics in the rat HXB/BXH family identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose

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