title: Structural basis for LMO2-driven recruitment of the SCL:E47bHLH heterodimer to hematopoietic-specific transcriptional targets.
abstract: Cell fate is governed by combinatorial actions of transcriptional regulators assembling into multiprotein complexes. However, the molecular details of how these complexes form are poorly understood. One such complex, which contains the basic-helix-loop-helix heterodimer SCL:E47 and bridging proteins LMO2:LDB1, critically regulates hematopoiesis and induces T cell leukemia. Here, we report the crystal structure of (SCL:E47)bHLH:LMO2:LDB1LID bound to DNA, providing a molecular account of the network of interactions assembling this complex. This reveals an unexpected role for LMO2. Upon binding to SCL, LMO2 induces new hydrogen bonds in SCL:E47, thereby strengthening heterodimer formation. This imposes a rotation movement onto E47 that weakens the heterodimer:DNA interaction, shifting the main DNA-binding activity onto additional protein partners. Along with biochemical analyses, this illustrates, at an atomic level, how hematopoietic-specific SCL sequesters ubiquitous E47 and associated cofactors and supports SCL's reported DNA-binding-independent functions. Importantly, this work will drive the design of small molecules inhibiting leukemogenic processes.
authors.affiliation: Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Kamel
authors.initials: K
authors.lastname: El Omari
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Hoosdally
authors.forename: Kapil
authors.initials: K
authors.lastname: Tuladhar
authors.forename: Dimple
authors.initials: D
authors.lastname: Karia
authors.forename: Elisa
authors.initials: E
authors.lastname: Hall-Ponselé
authors.forename: Olga
authors.initials: O
authors.lastname: Platonova
authors.forename: Paresh
authors.initials: P
authors.lastname: Vyas
authors.forename: Roger
authors.initials: R
authors.lastname: Patient
authors.forename: Catherine
authors.initials: C
authors.lastname: Porcher
authors.forename: Erika J
authors.initials: EJ
authors.lastname: Mancini
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D057809:HEK293 Cells; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D060588:LIM Domain Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D055503:Protein Multimerization; D014158:Transcription, Genetic; D015027:Zebrafish
chemical_list: D060588:LIM Domain Proteins; D004247:DNA