Chaperonin TRiC/CCT Recognizes Fusion Oncoprotein AML1-ETO through Subunit-Specific Interactions

Area of Science:

• Molecular Biology
• Cell Biology
• Cancer Research

Background:

• The AML1-ETO oncoprotein drives acute myeloid leukemia (AML) by disrupting normal gene expression during myeloid development.
• AML1-ETO interacts with the TRiC/CCT chaperonin, a cellular complex involved in protein folding.
• This interaction, particularly involving the AML1-ETO DNA-binding domain (AML1-175), is critical for AML1-ETO's synthesis, folding, and function.

Purpose of the Study:

• To elucidate the structural basis of the interaction between AML1-ETO and the TRiC/CCT chaperonin complex.
• To understand how TRiC/CCT influences the folding and activity of the AML1-ETO oncoprotein.

Main Methods:

• Single-particle cryo-electron microscopy (cryo-EM) was employed to visualize the complex.
• A folding intermediate of the AML1-ETO DNA-binding domain (AML1-175) was used to form a stable complex with apo-TRiC.

Main Results:

• A stable complex formed between the AML1-175 folding intermediate and apo-TRiC.
• The cryo-EM structure revealed that AML1-175 directly binds to specific TRiC subunits.
• The interaction occurs when TRiC is in its open conformation.

Conclusions:

• The TRiC/CCT chaperonin directly recognizes and binds to a folding intermediate of the AML1-ETO oncoprotein.
• This structural insight provides a mechanistic understanding of how TRiC/CCT facilitates AML1-ETO folding and contributes to AML pathogenesis.
• Targeting this interaction could offer a novel therapeutic strategy for AML.