{"doi":"10.1126/sciadv.adj8083","title":"Structural insights into the formation of repulsive netrin guidance complexes","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.","journal":"Science Advances","year":2024,"id":455358,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9555,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":402017,"name":"Ev L. Nichols","orcid":"0000-0001-9835-9107","position":1,"is_corresponding":false},{"id":1279186,"name":"Robert G. Smock","orcid":"0009-0005-7111-6013","position":2,"is_corresponding":false},{"id":430273,"name":"Jesse B. Hopkins","orcid":"0000-0001-8554-8072","position":3,"is_corresponding":false},{"id":237169,"name":"Juan L. Mendoza","orcid":"0000-0001-6972-7476","position":4,"is_corresponding":false},{"id":997378,"name":"Rob Meijers","orcid":"0000-0003-2872-6279","position":5,"is_corresponding":false},{"id":314620,"name":"Kang Shen","orcid":"0000-0003-4059-8249","position":6,"is_corresponding":false},{"id":350195,"name":"Engin Özkan","orcid":"0000-0002-0263-6729","position":7,"is_corresponding":false},{"id":392266,"name":"Jessica M. Priest","orcid":"0000-0001-7511-6284","position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":null,"created_at":"2026-07-19T02:03:17.458329Z","pmid":"38363837","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}