Structure of the Human TELO2-TTI1-TTI2 Complex.

Phosphatidylinositol 3-kinase-related protein kinases (PIKKs) play critical roles in various metabolic pathways related to cell proliferation and survival. The TELO2-TTI1-TTI2 (TTT) complex has been proposed to recognize newly synthesized PIKKs and to deliver them to the R2TP complex (RUVBL1-RUVBL2-RPAP3-PIH1D1) and the heat shock protein 90 chaperone, thereby supporting their folding ...
and assembly. Here, we determined the cryo-EM structure of the TTT complex at an average resolution of 4.2 A. We describe the full-length structures of TTI1 and TELO2, and a partial structure of TTI2. All three proteins form elongated helical repeat structures. TTI1 provides a platform on which TELO2 and TTI2 bind to its central region and C-terminal end, respectively. The TELO2 C-terminal domain (CTD) is required for the interaction with TTI1 and recruitment of Ataxia-telangiectasia mutated (ATM). The N- and C-terminal segments of TTI1 recognize the FRAP-ATM-TRRAP (FAT) domain and the N-terminal HEAT repeats of ATM, respectively. The TELO2 CTD and TTI1 N- and C-terminal segments are required for cell survival in response to ionizing radiation.
Mesh Terms:
ATPases Associated with Diverse Cellular Activities, Adaptor Proteins, Signal Transducing, Apoptosis Regulatory Proteins, Carrier Proteins, Cryoelectron Microscopy, DNA Helicases, HSP90 Heat-Shock Proteins, Humans, Intracellular Signaling Peptides and Proteins, Models, Molecular, Molecular Chaperones, Nuclear Proteins, Phosphatidylinositol 3-Kinase, Protein Conformation, Protein Folding, Protein Stability, Saccharomyces cerevisiae Proteins, Telomere-Binding Proteins
J Mol Biol
Date: Dec. 30, 2021
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