title: Leukemia fusion target AF9 is an intrinsically disordered transcriptional regulator that recruits multiple partners via coupled folding and binding.
abstract: Mixed lineage leukemia (MLL) fusion proteins cause oncogenic transformation of hematopoietic cells by constitutive recruitment of elongation factors to HOX promoters, resulting in overexpression of target genes. The structural basis of transactivation by MLL fusion partners remains undetermined. We show that the ANC1 homology domain (AHD) of AF9, one of the most common MLL translocation partners, is intrinsically disordered and recruits multiple transcription factors through coupled folding and binding. We determined the structure of the AF9 AHD in complex with the elongation factor AF4 and show that aliphatic residues, which are conserved in each of the AF9 binding partners, form an integral part of the hydrophobic core of the complex. Nuclear magnetic resonance relaxation measurements show that AF9 retains significant dynamic behavior which may facilitate exchange between disordered partners. We propose that AF9 functions as a signaling hub that regulates transcription through dynamic recruitment of cofactors in normal hematopoiesis and in acute leukemia.
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Benjamin I
authors.initials: BI
authors.lastname: Leach
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Aravinda
authors.initials: A
authors.lastname: Kuntimaddi
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Schmidt
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Cierpicki
authors.affiliation: Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Johnson
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA; Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA. Electronic address: jhb4v@virginia.edu.
authors.forename: John H
authors.initials: JH
authors.lastname: Bushweller
mesh_terms: D000595:Amino Acid Sequence; D002942:Circular Dichroism; D004268:DNA-Binding Proteins / Q000737:chemistry*; D005454:Fluorescence Polarization; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D009687:Nuclear Proteins / Q000737:chemistry*; D011485:Protein Binding; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D035602:Transcriptional Elongation Factors
chemical_list: D004268:DNA-Binding Proteins; C489901:MLLT3 protein, human; D009687:Nuclear Proteins; D035602:Transcriptional Elongation Factors; C081449:AFF1 protein, human