Dlx5 Homeodomain: DNA Complex: Structure, Binding and Effect of Mutations Related to Split Hand and Foot Malformation Syndrome
Abstract
The Dlx5 homeodomain is a transcription factor related to the Drosophila Distal-less gene that is associated with breast and lung cancer, lymphoma, Rett syndrome and osteoporosis in humans. Mutations in the DLX5 gene have been linked to deficiencies in craniofacial and limb development in higher eukaryotes, including Split Hand and Foot Malformation-1 (SHFM-1) in humans. Our characterization of a Dlx5 homeodomain–(CGACTAATTAGTCG)2 complex by NMR spectroscopy paved the way for determination of its crystal structure at 1.85 Å resolution that enabled rationalization of the effects of disease-related mutations on the protein function. A remarkably subtle mutation, Q186H, is linked to SHFM-1; this change likely affects affinity of DNA binding by disrupting water-mediated interactions with the DNA major groove. A more subtle effect is implicated for the Q178P mutation, which is not in direct contact with the DNA. Our data indicate that these mutations diminish the ability of the Dlx5 homeodomain to recognize and bind target DNAs, and likely destabilize the formation of functional complexes.
- Authors:
-
- Scripps Research Inst., La Jolla, CA (United States). Dept. of Integrative Structural and Computational Biology
- SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
- Univ. of California, San Francisco, CA (United States). Dept. of Biochemistry and Biophysics
- Scripps Research Inst., La Jolla, CA (United States). Dept. of Integrative Structural and Computational Biology; Scripps Research Inst., La Jolla, CA (United States). Skaggs Inst. for Chemical Biology; Federal Inst. of Technology (ETH), Zurich (Switzerland). Inst. of Molecular Biology and Biophysics
- Publication Date:
- Research Org.:
- SLAC National Accelerator Lab., Menlo Park, CA (United States)
- Sponsoring Org.:
- National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER)
- OSTI Identifier:
- 1256506
- Alternate Identifier(s):
- OSTI ID: 1346260
- Grant/Contract Number:
- U54 GM094586; AC02-76SF00515; P41GM103393; P41RR001209
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Molecular Biology
- Additional Journal Information:
- Journal Volume: 428; Journal Issue: 6; Journal ID: ISSN 0022-2836
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; NMR spectroscopy; SHFM-1 syndrome; protein:DNA complex
Citation Formats
Proudfoot, Andrew, Axelrod, Herbert L., Geralt, Michael, Fletterick, Robert J., Yumoto, Fumiaki, Deacon, Ashley M., Elsliger, Marc-André, Wilson, Ian A., Wüthrich, Kurt, and Serrano, Pedro. Dlx5 Homeodomain: DNA Complex: Structure, Binding and Effect of Mutations Related to Split Hand and Foot Malformation Syndrome. United States: N. p., 2016.
Web. doi:10.1016/j.jmb.2016.01.023.
Proudfoot, Andrew, Axelrod, Herbert L., Geralt, Michael, Fletterick, Robert J., Yumoto, Fumiaki, Deacon, Ashley M., Elsliger, Marc-André, Wilson, Ian A., Wüthrich, Kurt, & Serrano, Pedro. Dlx5 Homeodomain: DNA Complex: Structure, Binding and Effect of Mutations Related to Split Hand and Foot Malformation Syndrome. United States. https://doi.org/10.1016/j.jmb.2016.01.023
Proudfoot, Andrew, Axelrod, Herbert L., Geralt, Michael, Fletterick, Robert J., Yumoto, Fumiaki, Deacon, Ashley M., Elsliger, Marc-André, Wilson, Ian A., Wüthrich, Kurt, and Serrano, Pedro. Fri .
"Dlx5 Homeodomain: DNA Complex: Structure, Binding and Effect of Mutations Related to Split Hand and Foot Malformation Syndrome". United States. https://doi.org/10.1016/j.jmb.2016.01.023. https://www.osti.gov/servlets/purl/1256506.
@article{osti_1256506,
title = {Dlx5 Homeodomain: DNA Complex: Structure, Binding and Effect of Mutations Related to Split Hand and Foot Malformation Syndrome},
author = {Proudfoot, Andrew and Axelrod, Herbert L. and Geralt, Michael and Fletterick, Robert J. and Yumoto, Fumiaki and Deacon, Ashley M. and Elsliger, Marc-André and Wilson, Ian A. and Wüthrich, Kurt and Serrano, Pedro},
abstractNote = {The Dlx5 homeodomain is a transcription factor related to the Drosophila Distal-less gene that is associated with breast and lung cancer, lymphoma, Rett syndrome and osteoporosis in humans. Mutations in the DLX5 gene have been linked to deficiencies in craniofacial and limb development in higher eukaryotes, including Split Hand and Foot Malformation-1 (SHFM-1) in humans. Our characterization of a Dlx5 homeodomain–(CGACTAATTAGTCG)2 complex by NMR spectroscopy paved the way for determination of its crystal structure at 1.85 Å resolution that enabled rationalization of the effects of disease-related mutations on the protein function. A remarkably subtle mutation, Q186H, is linked to SHFM-1; this change likely affects affinity of DNA binding by disrupting water-mediated interactions with the DNA major groove. A more subtle effect is implicated for the Q178P mutation, which is not in direct contact with the DNA. Our data indicate that these mutations diminish the ability of the Dlx5 homeodomain to recognize and bind target DNAs, and likely destabilize the formation of functional complexes.},
doi = {10.1016/j.jmb.2016.01.023},
journal = {Journal of Molecular Biology},
number = 6,
volume = 428,
place = {United States},
year = {Fri Jan 29 00:00:00 EST 2016},
month = {Fri Jan 29 00:00:00 EST 2016}
}
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