| Structural highlights
Disease
ROBO3_HUMAN Horizontal gaze palsy with progressive scoliosis. The disease is caused by variants affecting the gene represented in this entry.
Function
ROBO3_HUMAN Thought to be involved during neural development in axonal navigation at the ventral midline of the neural tube (By similarity). In spinal cord development plays a role in guiding commissural axons probably by preventing premature sensitivity to Slit proteins thus inhibiting Slit signaling through ROBO1 (By similarity). Required for hindbrain axon midline crossing (PubMed:15105459).[UniProtKB:Q9Z2I4][1]
Publication Abstract from PubMed
Axon pathfinding is critical for nervous system development, and it is orchestrated by molecular cues that activate receptors on the axonal growth cone. Robo family receptors bind Slit guidance cues to mediate axon repulsion. In mammals, the divergent family member Robo3 does not bind Slits, but instead signals axon repulsion from its own ligand, NELL2. Conversely, canonical Robos do not mediate NELL2 signaling. Here, we present the structures of NELL-Robo3 complexes, identifying a mode of ligand engagement for Robos that is orthogonal to Slit binding. We elucidate the structural basis for differential binding between NELL and Robo family members and show that NELL2 repulsive activity is a function of its Robo3 affinity and is enhanced by ligand trimerization. Our results reveal a mechanism of oligomerization-induced Robo activation for axon guidance and shed light on Robo family member ligand binding specificity, conformational variability, divergent modes of signaling, and evolution.
NELL2-Robo3 complex structure reveals mechanisms of receptor activation for axon guidance.,Pak JS, DeLoughery ZJ, Wang J, Acharya N, Park Y, Jaworski A, Ozkan E Nat Commun. 2020 Mar 20;11(1):1489. doi: 10.1038/s41467-020-15211-1. PMID:32198364[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Jen JC, Chan WM, Bosley TM, Wan J, Carr JR, Rüb U, Shattuck D, Salamon G, Kudo LC, Ou J, Lin DD, Salih MA, Kansu T, Al Dhalaan H, Al Zayed Z, MacDonald DB, Stigsby B, Plaitakis A, Dretakis EK, Gottlob I, Pieh C, Traboulsi EI, Wang Q, Wang L, Andrews C, Yamada K, Demer JL, Karim S, Alger JR, Geschwind DH, Deller T, Sicotte NL, Nelson SF, Baloh RW, Engle EC. Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science. 2004 Jun 4;304(5676):1509-13. PMID:15105459 doi:10.1126/science.1096437
- ↑ Pak JS, DeLoughery ZJ, Wang J, Acharya N, Park Y, Jaworski A, Özkan E. NELL2-Robo3 complex structure reveals mechanisms of receptor activation for axon guidance. Nat Commun. 2020 Mar 20;11(1):1489. PMID:32198364 doi:10.1038/s41467-020-15211-1
|
