Tel2 structure and function in the Hsp90-dependent maturation of mTOR and ATR complexes Journal Article
| Authors: | Takai, H.; Xie, Y.; De Lange, T.; Pavletich, N. P. |
| Article Title: | Tel2 structure and function in the Hsp90-dependent maturation of mTOR and ATR complexes |
| Abstract: | We reported previously that the stability of all mammalian phosphatidylinositol 3-kinase-related protein kinases (PIKKs) depends on their interaction with Tel2, the ortholog of yeast Tel2 and Caenorhabditis elegans Clk-2. Here we provide evidence that Tel2 acts with Hsp90 in the maturation of PIKK complexes. Quantitative immunoblotting showed that the abundance of Tel2 is low compared with the PIKKs, and Tel2 preferentially bound newly synthesized ATM, ATR, mTOR, and DNA-PKcs. Tel2 complexes contained, in addition to Tti1-Tti2, the Hsp90 chaperone, and inhibition of Hsp90 interfered with the interaction of Tel2 with the PIKKs. Analysis of in vivo labeled nascent protein complexes showed that Tel2 and Hsp90 mediate the formation of the mTOR TORC1 and TORC2 complexes and the association of ATR with ATRIP. The structure of yeast Tel2, reported here, shows that Tel2 consists of HEAT-like helical repeats that assemble into two separate a-solenoids. Through mutagenesis, we identify a surface patch of conserved residues involved in binding to the Tti1-Tti2 complex in vitro. In vivo, mutation of this conserved patch affects cell growth, levels of PIKKs, and ATM/ATR-mediated checkpoint signaling, highlighting the importance of Tti1-Tti2 binding to the function of Tel2. Taken together, our data suggest that the Tel2-Tti1-Tti2 complex is a PIKK-specific cochaperone for Hsp90. © 2010 by Cold Spring Harbor Laboratory Press. |
| Keywords: | controlled study; unclassified drug; human cell; nonhuman; protein function; mammalia; animals; mice; cells, cultured; protein; protein binding; in vivo study; in vitro study; structure-activity relationship; phosphatidylinositol 3 kinase; mice, transgenic; dna; protein processing; protein-serine-threonine kinases; quantitative analysis; intracellular signaling peptides and proteins; mammalian target of rapamycin; immunoblotting; atm protein; heat shock protein 90; hsp90 heat-shock proteins; caenorhabditis elegans; yeast; saccharomyces cerevisiae proteins; protein structure; atr; atr protein; mutagenesis; mtor; hsp90; maturation; structure; orthology; solenoidea; dna protein complex; telomere-binding proteins; pikk; tel2; tel2 protein |
| Journal Title: | Genes and Development |
| Volume: | 24 |
| Issue: | 18 |
| ISSN: | 0890-9369 |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Date Published: | 2010-09-15 |
| Start Page: | 2019 |
| End Page: | 2030 |
| Language: | English |
| DOI: | 10.1101/gad.1956410 |
| PUBMED: | 20801936 |
| PROVIDER: | scopus |
| PMCID: | PMC2939364 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 3" - "Export Date: 20 April 2011" - "CODEN: GEDEE" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work