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Structure of the Elk-1–DNA complex reveals how DNA-distal residues affect ETS domain recognition of DNA

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Abstract

SAP-1 and Elk-1 are members of a large group of eukaryotic transcription factors that contain a conserved ETS DNA binding domain and that cooperate with the serum response factor (SRF) to activate transcription of the c-fos protooncogene. Despite the high degree of sequence similarity, which includes an identical amino acid sequence for the DNA recognition helix within the ETS domain of these proteins, they exhibit different DNA binding properties. Here we report the 2.1 Å crystal structure of the ETS domain of Elk-1 bound to a high affinity E74 DNA (E74DNA) site and compare it to a SAP-1–E74DNA complex. This comparison reveals that the differential DNA binding properties of these proteins are mediated by non-conserved residues distal to the DNA binding surface that function to orient conserved residues in the DNA recognition helix for protein-specific DNA contacts. As a result, nearly one-third of the interactions between the protein recognition helix and the DNA are different between the SAP-1 and Elk-1 DNA complexes. Taken together, these studies reveal a novel mechanism for the modulation of DNA binding specificity within a conserved DNA binding domain, and have implications for how highly homologous ETS proteins exhibit differential DNA-binding properties.

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Figure 1: The Elk-1 ETS domain, its DNA target site and protein–DNA interactions.
Figure 2: Overall structure of the Elk-1–E74DNA complex.
Figure 3: Comparison of protein–DNA contacts between Elk-1 and SAP-1.
Figure 4: Indirect effects of Asp 38 and Asp 69 on DNA recognition by Elk-1.

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Acknowledgements

We thank R. Treisman (Imperial Cancer Research Fund) for providing the pElk-1 plasmid, and R. Venkataramani, X. Li and R. Trievel for collecting data at NSLS and useful discussions. This work was supported by a grant from NIH and ACS to R.M.

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Author notes

  1. Benjamin Vaessen

    Present address: Department of Microbiology, University of Minnesota, Minneapolis, Minnesota, 55455, USA

  2. Yi Mo and Benjamin Vaessen: These authors contributed equally to the work.

Authors and Affiliations

  1. The Wistar Institute, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Yi Mo, Benjamin Vaessen, Karen Johnston & Ronen Marmorstein

  2. Department of Chemistry, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Yi Mo, Benjamin Vaessen & Ronen Marmorstein

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  1. Yi Mo
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  2. Benjamin Vaessen
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  3. Karen Johnston
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  4. Ronen Marmorstein
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Correspondence to Ronen Marmorstein.

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Mo, Y., Vaessen, B., Johnston, K. et al. Structure of the Elk-1–DNA complex reveals how DNA-distal residues affect ETS domain recognition of DNA. Nat Struct Mol Biol 7, 292–297 (2000). https://doi.org/10.1038/74055

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