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

DOI: 10.1038/srep03643 DOI Help
PMID: 24407558 PMID Help

Authors: Helen Sewell (University of Leeds) , Tomoyuki Tanaka (University of Leeds) , Kamel El Omari (University of Oxford) , Erika Mancini (University of Oxford) , A. Cruz (University of Oxford) , N. Fernandez-Fuentes (University of Leeds) , J. Chambers (University of Oxford) , T. H. Rabbitts (University of Leeds)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Scientific Reports , VOL 4

State: Published (Approved)
Published: January 2014

Open Access Open Access

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.

Journal Keywords: Signal; Crystallization; Crystallography; X-Ray; LIM; Models; Molecular; Mutation; Protein; Proto-Oncogene; Transcription; Genetic

Diamond Keywords: Leukaemia

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I02-Macromolecular Crystallography

Added On: 15/01/2014 13:11

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)