Structural insights into the formation of repulsive netrin guidance complexes

Priest, Jessica M.; Nichols, Ev L.; Smock, Robert G.; Hopkins, Jesse B.; Mendoza, Juan L.; Meijers, Rob; Shen, Kang; Özkan, Engin

doi:10.1126/sciadv.adj8083

Title: Structural insights into the formation of repulsive netrin guidance complexes

Journal Article · 16 February 2024 · Science Advances

DOI: https://doi.org/10.1126/sciadv.adj8083 · OSTI ID:2471051

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University of Chicago, IL (United States)
Stanford University, CA (United States)
European Molecular Biology Laboratory (EMBL), Hamburg (Germany)
Argonne National Laboratory (ANL), Argonne, IL (United States); Illinois Institute of Technology, Chicago, IL (United States)
European Molecular Biology Laboratory (EMBL), Hamburg (Germany); Institute for Protein Innovation (IPI), Boston, MA (United States)

Netrins dictate attractive and repulsive responses during axon growth and cell migration, where the presence of the receptor Uncoordinated-5 (UNC-5) on target cells results in repulsion. Here, we showed that UNC-5 is a heparin-binding protein, determined its structure bound to a heparin fragment, and could modulate UNC-5–heparin affinity using a directed evolution platform or structure-based rational design. We demonstrated that UNC-5 and UNC-6/netrin form a large, stable, and rigid complex in the presence of heparin, and heparin and UNC-5 exclude the attractive UNC-40/DCC receptor from binding to UNC-6/netrin to a large extent. Caenorhabditis elegans with a heparin-binding–deficient UNC-5 fail to establish proper gonad morphology due to abrogated cell migration, which relies on repulsive UNC-5 signaling in response to UNC-6. Combining UNC-5 mutations targeting heparin and UNC-6/netrin contacts results in complete cell migration and axon guidance defects. Our findings establish repulsive netrin responses to be mediated through a glycosaminoglycan-regulated macromolecular complex.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)

Sponsoring Organization:: H2020 European Research Council; National Cancer Institute; National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); National Science Foundation (NSF); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-05CH11231; AC02-06CH11357

OSTI ID:: 2471051

Journal Information:: Science Advances, Journal Name: Science Advances Journal Issue: 7 Vol. 10; ISSN 2375-2548

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

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