title: Chaperonin TRiC/CCT Modulates the Folding and Activity of Leukemogenic Fusion Oncoprotein AML1-ETO.
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.
authors.affiliation: From the Verna and Marrs McLean Department of Biochemistry and Molecular Biology and.
authors.forename: Soung-Hun
authors.initials: SH
authors.lastname: Roh
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, and.
authors.forename: Moses
authors.initials: M
authors.lastname: Kasembeli
authors.affiliation: From the Verna and Marrs McLean Department of Biochemistry and Molecular Biology and.
authors.forename: Jesús G
authors.initials: JG
authors.lastname: Galaz-Montoya
authors.affiliation: National Bio-Organic Biomedical Mass Spectrometry Resource Center, University of California, San Francisco, California 94158.
authors.forename: Mike
authors.initials: M
authors.lastname: Trnka
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, and.
authors.forename: Wilson Chun-Yu
authors.initials: WC
authors.lastname: Lau
authors.affiliation: National Bio-Organic Biomedical Mass Spectrometry Resource Center, University of California, San Francisco, California 94158.
authors.forename: Alma
authors.initials: A
authors.lastname: Burlingame
authors.affiliation: From the Verna and Marrs McLean Department of Biochemistry and Molecular Biology and wah@bcm.edu.
authors.forename: Wah
authors.initials: W
authors.lastname: Chiu
authors.affiliation: 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.
authors.forename: David J
authors.initials: DJ
authors.lastname: Tweardy
mesh_terms: D000818:Animals; D002417:Cattle; D002470:Cell Survival; D056404:Chaperonin Containing TCP-1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D050676:Core Binding Factor Alpha 2 Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D021122:Protein Subunits; D000075142:RUNX1 Translocation Partner 1 Protein; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D012156:Reticulocytes / Q000378:metabolism
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D018840:HSP70 Heat-Shock Proteins; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D010446:Peptide Fragments; D021122:Protein Subunits; D000075142:RUNX1 Translocation Partner 1 Protein; D011993:Recombinant Fusion Proteins; C533304:TCP1 protein, human; D056404:Chaperonin Containing TCP-1
keywords: AML1-ETO; TRiC/CCT; chaperone; chaperonin; fusion protein; leukemia; protein folding