Abstract
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 Å. 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.
Keywords:
PIKKs; TELO2-TTI1-TTI2 complex; cryo-EM; protein folding; protein stability.
Copyright © 2021 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATPases Associated with Diverse Cellular Activities
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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Carrier Proteins
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Cryoelectron Microscopy
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DNA Helicases
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HSP90 Heat-Shock Proteins / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins / chemistry*
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Models, Molecular
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Molecular Chaperones / metabolism
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Nuclear Proteins
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Phosphatidylinositol 3-Kinase / chemistry
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Phosphatidylinositol 3-Kinase / genetics
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Phosphatidylinositol 3-Kinase / metabolism
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Protein Conformation
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Protein Folding
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Protein Stability
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Saccharomyces cerevisiae Proteins
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Telomere-Binding Proteins / chemistry*
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Telomere-Binding Proteins / genetics
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Telomere-Binding Proteins / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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Carrier Proteins
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HSP90 Heat-Shock Proteins
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Intracellular Signaling Peptides and Proteins
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Molecular Chaperones
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Nuclear Proteins
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PIH1D1 protein, human
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RPAP3 protein, human
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Saccharomyces cerevisiae Proteins
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TELO2 protein, human
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TTI2 protein, human
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Telomere-Binding Proteins
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Tti1 protein, human
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transformation-transcription domain-associated protein
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Phosphatidylinositol 3-Kinase
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ATPases Associated with Diverse Cellular Activities
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DNA Helicases
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RUVBL1 protein, human
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RUVBL2 protein, human