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Sci Rep. 2014 Jan 10;4:3643. doi: 10.1038/srep03643.

Conformational flexibility of the oncogenic protein LMO2 primes the formation of the multi-protein transcription complex.

Author information

1
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].
2
1] Leeds Institute of Molecular Medicine Wellcome Trust Brenner Building St. James's University Hospital University of Leeds Leeds, LS9 7TF, UK [2] [3].
3
1] Wellcome Trust Centre for Human Genetics Division of Structural Biology University of Oxford Headington, Oxford OX3 7BN, UK [2].
4
Wellcome Trust Centre for Human Genetics Division of Structural Biology University of Oxford Headington, Oxford OX3 7BN, UK.
5
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.
6
1] Leeds Institute of Molecular Medicine Wellcome Trust Brenner Building St. James's University Hospital University of Leeds Leeds, LS9 7TF, UK [2].

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.

PMID:
24407558
PMCID:
PMC3887373
DOI:
10.1038/srep03643
[Indexed for MEDLINE]
Free PMC Article
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