title: Conformational flexibility of the oncogenic protein LMO2 primes the formation of the multi-protein transcription complex.
abstract: LMO2 was discovered via chromosomal translocations in T-cell leukaemia and shown normally to be essential for haematopoiesis. LMO2 is made up of two LIM only domains (thus it is a LIM-only protein) and forms a bridge in a multi-protein complex. We have studied the mechanism of formation of this complex using a single domain antibody fragment that inhibits LMO2 by sequestering it in a non-functional form. The crystal structure of LMO2 with this antibody fragment has been solved revealing a conformational difference in the positioning and angle between the two LIM domains compared with its normal binding. This contortion occurs by bending at a central helical region of LMO2. This is a unique mechanism for inhibiting an intracellular protein function and the structural contusion implies a model in which newly synthesized, intrinsically disordered LMO2 binds to a partner protein nucleating further interactions and suggests approaches for therapeutic targeting of LMO2.
authors.affiliation: 1] Weatherall Institute of Molecular Medicine MRC Molecular Haematology Unit University of Oxford John Radcliffe Hospital Oxford OX3 9DS, UK [2] Leeds Institute of Molecular Medicine Wellcome Trust Brenner Building St. James's University Hospital University of Leeds Leeds, LS9 7TF, UK [3] [4].
authors.forename: H
authors.initials: H
authors.lastname: Sewell
authors.affiliation: 1] Leeds Institute of Molecular Medicine Wellcome Trust Brenner Building St. James's University Hospital University of Leeds Leeds, LS9 7TF, UK [2] [3].
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: 1] Wellcome Trust Centre for Human Genetics Division of Structural Biology University of Oxford Headington, Oxford OX3 7BN, UK [2].
authors.forename: K
authors.initials: K
authors.lastname: El Omari
authors.affiliation: Wellcome Trust Centre for Human Genetics Division of Structural Biology University of Oxford Headington, Oxford OX3 7BN, UK.
authors.forename: E J
authors.initials: EJ
authors.lastname: Mancini
authors.affiliation: 1] Weatherall Institute of Molecular Medicine MRC Molecular Haematology Unit University of Oxford John Radcliffe Hospital Oxford OX3 9DS, UK [2] Leeds Institute of Molecular Medicine Wellcome Trust Brenner Building St. James's University Hospital University of Leeds Leeds, LS9 7TF, UK.
authors.forename: A
authors.initials: A
authors.lastname: Cruz
authors.affiliation: 1] Leeds Institute of Molecular Medicine Wellcome Trust Brenner Building St. James's University Hospital University of Leeds Leeds, LS9 7TF, UK [2].
authors.forename: N
authors.initials: N
authors.lastname: Fernandez-Fuentes
authors.affiliation: 1] Weatherall Institute of Molecular Medicine MRC Molecular Haematology Unit University of Oxford John Radcliffe Hospital Oxford OX3 9DS, UK [2] Leeds Institute of Molecular Medicine Wellcome Trust Brenner Building St. James's University Hospital University of Leeds Leeds, LS9 7TF, UK.
authors.forename: J
authors.initials: J
authors.lastname: Chambers
authors.affiliation: 1] Weatherall Institute of Molecular Medicine MRC Molecular Haematology Unit University of Oxford John Radcliffe Hospital Oxford OX3 9DS, UK [2] Leeds Institute of Molecular Medicine Wellcome Trust Brenner Building St. James's University Hospital University of Leeds Leeds, LS9 7TF, UK.
authors.forename: T H
authors.initials: TH
authors.lastname: Rabbitts
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics; D003460:Crystallization; D018360:Crystallography, X-Ray; D060588:LIM Domain Proteins / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D011518:Proto-Oncogene Proteins