Sewell_et_al_(2014).pdf (1.57 MB)
Conformational flexibility of the oncogenic protein LMO2 primes the formation of the multi-protein transcription complex
journal contribution
posted on 2023-06-08, 19:50 authored by H Sewell, T Tanaka, K E Omari, Erika ManciniErika Mancini, A Cruz, N Fernandez-Fuentes, J Chambers, T H RabbittsLMO2 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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Publication status
- Published
File Version
- Published version
Journal
Scientific ReportsISSN
2045-2322Publisher
Nature Publishing GroupExternal DOI
Issue
1Volume
4Article number
a3643Department affiliated with
- Biochemistry Publications
Research groups affiliated with
- Haematology Research Group Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2015-01-30First Open Access (FOA) Date
2015-01-30First Compliant Deposit (FCD) Date
2015-01-30Usage metrics
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