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J Biol Chem. 2016 Feb 26;291(9):4732-41. doi: 10.1074/jbc.M115.684878. Epub 2015 Dec 24.

Chaperonin TRiC/CCT Modulates the Folding and Activity of Leukemogenic Fusion Oncoprotein AML1-ETO.

Author information

1
From the Verna and Marrs McLean Department of Biochemistry and Molecular Biology and.
2
Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, and.
3
National Bio-Organic Biomedical Mass Spectrometry Resource Center, University of California, San Francisco, California 94158.
4
From the Verna and Marrs McLean Department of Biochemistry and Molecular Biology and wah@bcm.edu.
5
From the Verna and Marrs McLean Department of Biochemistry and Molecular Biology and Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, and dtweardy@bcm.edu.

Abstract

AML1-ETO is the most common fusion oncoprotein causing acute myeloid leukemia (AML), a disease with a 5-year survival rate of only 24%. AML1-ETO functions as a rogue transcription factor, altering the expression of genes critical for myeloid cell development and differentiation. Currently, there are no specific therapies for AML1-ETO-positive AML. While known for decades to be the translational product of a chimeric gene created by the stable chromosome translocation t(8;21)(q22;q22), it is not known how AML1-ETO achieves its native and functional conformation or whether this process can be targeted for therapeutic benefit. Here, we show that the biosynthesis and folding of the AML1-ETO protein is facilitated by interaction with the essential eukaryotic chaperonin TRiC (or CCT). We demonstrate that a folding intermediate of AML1-ETO binds to TRiC directly, mainly through its β-strand rich, DNA-binding domain (AML-(1-175)), with the assistance of HSP70. Our results suggest that TRiC contributes to AML1-ETO proteostasis through specific interactions between the oncoprotein's DNA-binding domain, which may be targeted for therapeutic benefit.

KEYWORDS:

AML1-ETO; TRiC/CCT; chaperone; chaperonin; fusion protein; leukemia; protein folding

PMID:
26706127
PMCID:
PMC4813495
[Available on 2017-02-26]
DOI:
10.1074/jbc.M115.684878
[Indexed for MEDLINE]
Free PMC Article

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