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bioRxiv · 10.1101/2022.03.28.485992

Molecular basis of DNA recognition by the HMG-box-C1 module of Capicua

Webb, J.·Gnann, A. D.·Liew, J. J. M.·Patterson, M.·Paul, S.·Fores, M.·Jimenez, G.·Veraksa, A.·Dowling, D. P.
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Abstract

The HMG-box protein Capicua (CIC) is an evolutionarily conserved transcriptional repressor with key functions in development and disease-associated processes. CIC binds DNA using an exclusive mechanism that requires both its HMG-box and a separate domain called C1, but how these domains cooperate to recognize specific DNA sequences is not known. Here we report the crystal structure of the human CIC HMG-box and C1 domains in complex with an 18-base-pair DNA oligomer containing a consensus octameric CIC binding site. We find that both protein domains adopt independent tri-helical structures that pack against opposite sides of the DNA helix. The C1 domain in particular folds into a helix-turn-helix (HTH) structure that resembles the FF phosphoprotein binding domain. It inserts into the major groove of the DNA and plays a direct role in enhancing both the affinity and sequence specificity of CIC DNA binding. Our results reveal a unique bipartite protein module, ensuring highly specific DNA recognition by CIC, and show how this mechanism is disrupted by cancer mutations affecting either the HMG-box or C1 domains.

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Webb, J., Gnann, A. D., Liew, J. J. M., Patterson, M., Paul, S., Fores, M., Jimenez, G., Veraksa, A., Dowling, D. P.. 2022-03-29. Molecular basis of DNA recognition by the HMG-box-C1 module of Capicua. https://doi.org/10.1101/2022.03.28.485992

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