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Structure of the Human TELO2-TTI1-TTI2 Complex

Youngran Kim1, Junhyeon Park1, So Young Joo2

  • 1Department of Life Science, Pohang University of Science and Technology, Pohang 37673, South Korea.

Journal of Molecular Biology
|November 28, 2021
PubMed

Insights

The TELO2-TTI1-TTI2 complex

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Cellular Metabolism

Background:

  • Phosphatidylinositol 3-kinase-related protein kinases (PIKKs) are crucial for cell proliferation and survival.
  • The TELO2-TTI1-TTI2 (TTT) complex is implicated in the maturation of newly synthesized PIKKs.
  • The TTT complex facilitates PIKK delivery to the R2TP complex and HSP90 chaperone for proper folding and assembly.

Purpose of the Study:

  • To elucidate the structural basis of the TELO2-TTI1-TTI2 (TTT) complex.
  • To understand the TTT complex's role in the maturation of PIKKs.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was employed to determine the structure of the TTT complex.
  • Full-length structures of TTI1 and TELO2, and a partial structure of TTI2 were resolved.

Main Results:

  • The cryo-EM structure of the TTT complex was determined at 4.2 Å resolution.
  • TTI1, TELO2, and TTI2 form elongated helical repeat structures.
  • TTI1 acts as a scaffold, binding TELO2 and TTI2 at distinct regions.
  • Specific domains of TELO2 and TTI1 interact with Ataxia-telangiectasia mutated (ATM).

Conclusions:

  • The TTT complex's structure reveals its scaffolding role in PIKK maturation.
  • Interactions between TTT complex components and ATM are critical for PIKK assembly.
  • The TELO2 CTD and TTI1 N/C-terminal segments are essential for cellular survival following ionizing radiation exposure.
Keywords:
PIKKsTELO2-TTI1-TTI2 complexcryo-EMprotein foldingprotein stability

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