title: Structure of the leukemia oncogene LMO2: implications for the assembly of a hematopoietic transcription factor complex.
abstract: The LIM only protein 2 (LMO2) is a key regulator of hematopoietic stem cell development whose ectopic expression in T cells leads to the onset of acute lymphoblastic leukemia. Through its LIM domains, LMO2 is thought to function as the scaffold for a DNA-binding transcription regulator complex, including the basic helix-loop-helix proteins SCL/TAL1 and E47, the zinc finger protein GATA-1, and LIM-domain interacting protein LDB1. To understand the role of LMO2 in the formation of this complex and ultimately to dissect its function in normal and aberrant hematopoiesis, we solved the crystal structure of LMO2 in complex with the LID domain of LDB1 at 2.4 Å resolution. We observe a largely unstructured LMO2 kept in register by the LID binding both LIM domains. Comparison of independently determined crystal structures of LMO2 reveals large movements around a conserved hinge between the LIM domains. We demonstrate that such conformational flexibility is necessary for binding of LMO2 to its partner protein SCL/TAL1 in vitro and for the function of this complex in vivo. These results, together with molecular docking and analysis of evolutionarily conserved residues, yield the first structural model of the DNA-binding complex containing LMO2, LDB1, SCL/TAL1, and GATA-1.
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, 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: 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: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D019143:Evolution, Molecular; D050982:GATA1 Transcription Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D060588:LIM Domain Proteins; D008667:Metalloproteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D016297:Mutagenesis, Site-Directed; D015513:Oncogene Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D009857:Oncogenes; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D050982:GATA1 Transcription Factor; D060588:LIM Domain Proteins; D008667:Metalloproteins; D046912:Multiprotein Complexes; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C494688:GATA1 protein, human; C486312:LDB1 protein, human; C085117:LMO2 protein, human; C067143:TAL1 protein, human