Structure of the human TIP60 complex.

Area of Science:

• Molecular Biology
• Structural Biology
• Biochemistry

Background:

• Mammalian TIP60 is a crucial enzyme involved in transcription, DNA repair, and cell cycle control.
• It possesses histone acetylation and histone dimer exchange activities.
• Understanding its structure is key to deciphering its diverse cellular functions.

Purpose of the Study:

• To determine the high-resolution cryo-electron microscopy structures of the human TIP60 complex.
• To elucidate the molecular architecture and subunit organization of TIP60.
• To provide insights into how TIP60 interacts with nucleosomes.

Main Methods:

• Cryo-electron microscopy (cryo-EM) at 3.2-Å resolution.
• Structural refinement of the human TIP60 complex, including core and TRRAP modules.
• Analysis of protein-protein interactions within the complex.

Main Results:

• The EP400 protein serves as a central scaffold, integrating motor, ARP, and TRRAP modules.
• Specific protein interactions define the assembly of the motor module (RUVBL1-RUVBL2 hexamer, EP400 ATPase, YL1) and the ARP module (ACTL6A-ACTB heterodimer, DMAP1, EPC1).
• The ARP module shows stable association with the motor module but flexible tethering to the TRRAP module, with an unengaged nucleosome positioned between the core and TRRAP modules.

Conclusions:

• The study reveals the detailed molecular architecture of the human TIP60 complex.
• The findings offer structural insights into the TIP60 complex's interaction with nucleosomes.
• This work lays the foundation for understanding TIP60's role in various cellular processes.