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Cell fate is governed by combinatorial actions of transcriptional regulators assembling into multiprotein complexes. However, the molecular details of how these complexes form are poorly understood. One such complex, which contains the basic-helix-loop-helix heterodimer SCL:E47 and bridging proteins LMO2:LDB1, critically regulates hematopoiesis and induces T cell leukemia. Here, we report the crystal structure of (SCL:E47)bHLH:LMO2:LDB1LID bound to DNA, providing a molecular account of the network of interactions assembling this complex. This reveals an unexpected role for LMO2. Upon binding to SCL, LMO2 induces new hydrogen bonds in SCL:E47, thereby strengthening heterodimer formation. This imposes a rotation movement onto E47 that weakens the heterodimer:DNA interaction, shifting the main DNA-binding activity onto additional protein partners. Along with biochemical analyses, this illustrates, at an atomic level, how hematopoietic-specific SCL sequesters ubiquitous E47 and associated cofactors and supports SCL's reported DNA-binding-independent functions. Importantly, this work will drive the design of small molecules inhibiting leukemogenic processes.

Original publication

DOI

10.1016/j.celrep.2013.06.008

Type

Journal article

Journal

Cell Rep

Publication Date

11/07/2013

Volume

4

Pages

135 - 147

Keywords

Amino Acid Sequence, Animals, Binding Sites, Cell Line, Tumor, DNA, HEK293 Cells, Hematopoiesis, Humans, LIM Domain Proteins, Mice, Molecular Docking Simulation, Molecular Dynamics Simulation, Molecular Sequence Data, Mutation, Protein Multimerization, Transcription, Genetic, Zebrafish