@article{TEXTUAL,
      recid = {11113},
      author = {Priest, Jessica M. and Nichols, Ev L. and Smock, Robert G.  and Hopkins, Jesse B. and Mendoza, Juan L. and Meijers, ROb  and Shen, Kang and Özkan, Engin},
      title = {Structural insights into the formation of repulsive netrin  guidance complexes},
      journal = {Science Advances},
      address = {2024-02-16},
      number = {TEXTUAL},
      abstract = {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.},
      url = {http://knowledge.uchicago.edu/record/11113},
}