Solution Structure of C. elegans UNC-6: A Nematode Paralogue of the Axon Guidance Protein Netrin-1 |
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| Authors: | Natalie Krahn Markus Meier Raphael Reuten Manuel Koch Joerg Stetefeld Trushar R. Patel |
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| Affiliation: | 1. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut;2. Department of Chemistry, University of Manitoba, Winnipeg, Manitoba, Canada;3. Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark;4. Institute for Dental Research and Oral Musculoskeletal Biology, Medical Faculty, University of Cologne, Cologne, Germany;5. Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany;6. Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada;7. Alberta RNA Research and Training Institute, Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Alberta, Canada;8. Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada;9. DiscoveryLab and Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada |
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| Abstract: | UNCoordinated-6 (UNC-6) was the first member of the netrin family to be discovered in Caenorhabditis elegans. With homology to human netrin-1, it is a key signaling molecule involved in directing axon migration in nematodes. Similar to netrin-1, UNC-6 interacts with multiple receptors (UNC-5 and UNC-40, specifically) to guide axon migration in development. As a result of the distinct evolutionary path of UNC-6 compared to vertebrate netrins, we decided to employ an integrated approach to study its solution behavior and compare it to the high-resolution structure we previously published on vertebrate netrins. Dynamic light scattering and analytical ultracentrifugation on UNC-6 (with and without its C-domain) solubilized in a low-ionic strength buffer suggested that UNC-6 forms high-order oligomers. An increase in the buffer ionic strength resulted in a more homogeneous preparation of UNC-6, that was used for subsequent solution x-ray scattering experiments. Our biophysical analysis of UNC-6 ΔC solubilized in a high-ionic strength buffer suggested that it maintains a similar head-to-stalk arrangement as netrins ?1 and ?4. This phenomenon is thought to play a role in the signaling behavior of UNC-6 and its ability to move throughout the extracellular matrix. |
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| Keywords: | Corresponding author |
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