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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2014
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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. |
format | Online Article Text |
id | pubmed-3887373 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
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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