Structure of the Human 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.