8EDI

Structure of C. elegans UNC-5 IG 1+2 Domains bound to Heparin dp4

Summary for 8EDI

• Entry DOI: 10.2210/pdb8edi/pdb
• Related: 8EDC 8EDK
• Descriptor: Netrin receptor unc-5, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, 4-deoxy-2-O-sulfo-alpha-L-threo-hex-4-enopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: cell surface receptor, axon guidance, signaling, glycoprotein, protein binding
• Biological source: Caenorhabditis elegans
• Total number of polymer chains: 2
• Total formula weight: 48669.65

Authors

Priest, J.M.,Ozkan, E. (deposition date: 2022-09-04, release date: 2023-01-11, Last modification date: 2024-11-20)

Primary citation

Priest, J.M.,Nichols, E.L.,Smock, R.G.,Hopkins, J.B.,Mendoza, J.L.,Meijers, R.,Shen, K.,Ozkan, E.
Structural insights into the formation of repulsive netrin guidance complexes.
Sci Adv, 10:eadj8083-eadj8083, 2024

PubMed 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. 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.

PubMed: 38363837
DOI: 10.1126/sciadv.adj8083

Experimental method

X-RAY DIFFRACTION (2.11 Å)