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

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 comp...

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Autores principales: Sewell, H., Tanaka, T., Omari, K. El, Mancini, E. J., Cruz, A., Fernandez-Fuentes, N., Chambers, J., Rabbitts, T. H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3887373/
https://www.ncbi.nlm.nih.gov/pubmed/24407558
http://dx.doi.org/10.1038/srep03643
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author Sewell, H.
Tanaka, T.
Omari, K. El
Mancini, E. J.
Cruz, A.
Fernandez-Fuentes, N.
Chambers, J.
Rabbitts, T. H.
author_facet Sewell, H.
Tanaka, T.
Omari, K. El
Mancini, E. J.
Cruz, A.
Fernandez-Fuentes, N.
Chambers, J.
Rabbitts, T. H.
author_sort Sewell, H.
collection PubMed
description 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.
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spelling pubmed-38873732014-01-10 Conformational flexibility of the oncogenic protein LMO2 primes the formation of the multi-protein transcription complex Sewell, H. Tanaka, T. Omari, K. El Mancini, E. J. Cruz, A. Fernandez-Fuentes, N. Chambers, J. Rabbitts, T. H. Sci Rep Article 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. Nature Publishing Group 2014-01-10 /pmc/articles/PMC3887373/ /pubmed/24407558 http://dx.doi.org/10.1038/srep03643 Text en Copyright © 2014, Macmillan Publishers Limited. All rights reserved http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Article
Sewell, H.
Tanaka, T.
Omari, K. El
Mancini, E. J.
Cruz, A.
Fernandez-Fuentes, N.
Chambers, J.
Rabbitts, T. H.
Conformational flexibility of the oncogenic protein LMO2 primes the formation of the multi-protein transcription complex
title Conformational flexibility of the oncogenic protein LMO2 primes the formation of the multi-protein transcription complex
title_full Conformational flexibility of the oncogenic protein LMO2 primes the formation of the multi-protein transcription complex
title_fullStr Conformational flexibility of the oncogenic protein LMO2 primes the formation of the multi-protein transcription complex
title_full_unstemmed Conformational flexibility of the oncogenic protein LMO2 primes the formation of the multi-protein transcription complex
title_short Conformational flexibility of the oncogenic protein LMO2 primes the formation of the multi-protein transcription complex
title_sort conformational flexibility of the oncogenic protein lmo2 primes the formation of the multi-protein transcription complex
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3887373/
https://www.ncbi.nlm.nih.gov/pubmed/24407558
http://dx.doi.org/10.1038/srep03643
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