8edc

Structure of C. elegans UNC-5 IG 1+2 DomainsStructure of C. elegans UNC-5 IG 1+2 Domains

Structural highlights

8edc is a 1 chain structure with sequence from Caenorhabditis elegans. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.89Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

UNC5_CAEEL Receptor for netrin (unc-6) required for axon guidance (PubMed:11454756, PubMed:8332188). Mediates axon repulsion of neuronal growth cones in the developing nervous system upon ligand binding (PubMed:11454756, PubMed:1384987, PubMed:8332188, PubMed:9473333). Axon migration is mediated by the secreted unc-6, which promotes attraction of neurons and axons through binding to the unc-40 receptor, while repulsion requires both unc-5 and unc-40 receptors (PubMed:11454756, PubMed:9473333). Involved in the ventral-dorsal and anterior-posterior migration of distal tip cells along the body, which may be mediated by Wnt receptor mom-5, ced-10/Rac, ced-12/ELMO and mig-2/RhoG (PubMed:10631179, PubMed:17716643, PubMed:26292279).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

Publication Abstract from PubMed

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.

Structural insights into the formation of repulsive netrin guidance complexes.,Priest JM, Nichols EL, Smock RG, Hopkins JB, Mendoza JL, Meijers R, Shen K, Ozkan E Sci Adv. 2024 Feb 16;10(7):eadj8083. doi: 10.1126/sciadv.adj8083. Epub 2024 Feb , 16. PMID:38363837^[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Su M, Merz DC, Killeen MT, Zhou Y, Zheng H, Kramer JM, Hedgecock EM, Culotti JG. Regulation of the UNC-5 netrin receptor initiates the first reorientation of migrating distal tip cells in Caenorhabditis elegans. Development. 2000 Feb;127(3):585-94. PMID:10631179
↑ Merz DC, Zheng H, Killeen MT, Krizus A, Culotti JG. Multiple signaling mechanisms of the UNC-6/netrin receptors UNC-5 and UNC-40/DCC in vivo. Genetics. 2001 Jul;158(3):1071-80. PMID:11454756
↑ Leung-Hagesteijn C, Spence AM, Stern BD, Zhou Y, Su MW, Hedgecock EM, Culotti JG. UNC-5, a transmembrane protein with immunoglobulin and thrombospondin type 1 domains, guides cell and pioneer axon migrations in C. elegans. Cell. 1992 Oct 16;71(2):289-99. PMID:1384987
↑ Zheng H, Coudiere L, Camia C, Colavita A, Culotti JG, Merz DC. C. elegans seu-1 encodes novel nuclear proteins that regulate responses to UNC-6/netrin guidance cues. Dev Biol. 2007 Oct 1;310(1):44-53. doi: 10.1016/j.ydbio.2007.07.014. Epub 2007 , Jul 24. PMID:17716643 doi:http://dx.doi.org/10.1016/j.ydbio.2007.07.014
↑ Levy-Strumpf N, Krizus M, Zheng H, Brown L, Culotti JG. The Wnt Frizzled Receptor MOM-5 Regulates the UNC-5 Netrin Receptor through Small GTPase-Dependent Signaling to Determine the Polarity of Migrating Cells. PLoS Genet. 2015 Aug 20;11(8):e1005446. doi: 10.1371/journal.pgen.1005446. , eCollection 2015 Aug. PMID:26292279 doi:http://dx.doi.org/10.1371/journal.pgen.1005446
↑ Hamelin M, Zhou Y, Su MW, Scott IM, Culotti JG. Expression of the UNC-5 guidance receptor in the touch neurons of C. elegans steers their axons dorsally. Nature. 1993 Jul 22;364(6435):327-30. PMID:8332188 doi:http://dx.doi.org/10.1038/364327a0
↑ Colavita A, Culotti JG. Suppressors of ectopic UNC-5 growth cone steering identify eight genes involved in axon guidance in Caenorhabditis elegans. Dev Biol. 1998 Feb 1;194(1):72-85. doi: 10.1006/dbio.1997.8790. PMID:9473333 doi:http://dx.doi.org/10.1006/dbio.1997.8790
↑ Priest JM, Nichols EL, Smock RG, Hopkins JB, Mendoza JL, Meijers R, Shen K, Özkan E. Structural insights into the formation of repulsive netrin guidance complexes. Sci Adv. 2024 Feb 16;10(7):eadj8083. PMID:38363837 doi:10.1126/sciadv.adj8083

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OCA

[1] Su M, Merz DC, Killeen MT, Zhou Y, Zheng H, Kramer JM, Hedgecock EM, Culotti JG. Regulation of the UNC-5 netrin receptor initiates the first reorientation of migrating distal tip cells in Caenorhabditis elegans. Development. 2000 Feb;127(3):585-94. PMID:10631179

[2] Merz DC, Zheng H, Killeen MT, Krizus A, Culotti JG. Multiple signaling mechanisms of the UNC-6/netrin receptors UNC-5 and UNC-40/DCC in vivo. Genetics. 2001 Jul;158(3):1071-80. PMID:11454756

[3] Leung-Hagesteijn C, Spence AM, Stern BD, Zhou Y, Su MW, Hedgecock EM, Culotti JG. UNC-5, a transmembrane protein with immunoglobulin and thrombospondin type 1 domains, guides cell and pioneer axon migrations in C. elegans. Cell. 1992 Oct 16;71(2):289-99. PMID:1384987

[4] Zheng H, Coudiere L, Camia C, Colavita A, Culotti JG, Merz DC. C. elegans seu-1 encodes novel nuclear proteins that regulate responses to UNC-6/netrin guidance cues. Dev Biol. 2007 Oct 1;310(1):44-53. doi: 10.1016/j.ydbio.2007.07.014. Epub 2007 , Jul 24. PMID:17716643 doi:http://dx.doi.org/10.1016/j.ydbio.2007.07.014

[5] Levy-Strumpf N, Krizus M, Zheng H, Brown L, Culotti JG. The Wnt Frizzled Receptor MOM-5 Regulates the UNC-5 Netrin Receptor through Small GTPase-Dependent Signaling to Determine the Polarity of Migrating Cells. PLoS Genet. 2015 Aug 20;11(8):e1005446. doi: 10.1371/journal.pgen.1005446. , eCollection 2015 Aug. PMID:26292279 doi:http://dx.doi.org/10.1371/journal.pgen.1005446

[6] Hamelin M, Zhou Y, Su MW, Scott IM, Culotti JG. Expression of the UNC-5 guidance receptor in the touch neurons of C. elegans steers their axons dorsally. Nature. 1993 Jul 22;364(6435):327-30. PMID:8332188 doi:http://dx.doi.org/10.1038/364327a0

[7] Colavita A, Culotti JG. Suppressors of ectopic UNC-5 growth cone steering identify eight genes involved in axon guidance in Caenorhabditis elegans. Dev Biol. 1998 Feb 1;194(1):72-85. doi: 10.1006/dbio.1997.8790. PMID:9473333 doi:http://dx.doi.org/10.1006/dbio.1997.8790

[8] Priest JM, Nichols EL, Smock RG, Hopkins JB, Mendoza JL, Meijers R, Shen K, Özkan E. Structural insights into the formation of repulsive netrin guidance complexes. Sci Adv. 2024 Feb 16;10(7):eadj8083. PMID:38363837 doi:10.1126/sciadv.adj8083

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