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NELL2-Robo3 complex structure reveals mechanisms of receptor activation for axon guidance.

<div class='caption-title'>Robo3.1 is necessary and sufficient for axon repulsion from NELL2.</div>
<div class='caption-title'>NELL2 EGF2–3 bind Robo3 FN1 to mediate complex formation.</div>
<div class='caption-title'>Crystal structure of the NELL2–Robo3 complex.</div>
Pak JS, DeLoughery ZJ, Wang J, Acharya N, Park Y, Jaworski A, Özkan E
OpenAccess logo Nat Commun 11 1489 (2020)
Related entries: 6pog, 6pol

Cited: 19 times
EuropePMC logo PMID: 32198364

Abstract

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.

Reviews citing this publication (7)

  1. New insights into the molecular mechanisms of axon guidance receptor regulation and signaling. Zang Y, Chaudhari K, Bashaw GJ. Curr Top Dev Biol 142 147-196 (2021)
  2. Roles and Mechanisms of Axon-Guidance Molecules in Alzheimer's Disease. Zhang L, Qi Z, Li J, Li M, Du X, Wang S, Zhou G, Xu B, Liu W, Xi S, Xu Z, Deng Y. Mol Neurobiol 58 3290-3307 (2021)
  3. Lysosomal Function and Axon Guidance: Is There a Meaningful Liaison? Manzoli R, Badenetti L, Rubin M, Moro E. Biomolecules 11 191 (2021)
  4. Role of Slit/Robo Signaling pathway in Bone Metabolism. Jiang L, Sun J, Huang D. Int J Biol Sci 18 1303-1312 (2022)
  5. Dorsal commissural axon guidance in the developing spinal cord. Alvarez S, Varadarajan SG, Butler SJ. Curr Top Dev Biol 142 197-231 (2021)
  6. Roles of Slit Ligands and Their Roundabout (Robo) Family of Receptors in Bone Remodeling. Niimi T. Adv Exp Med Biol 21 143-154 (2021)
  7. Structure and evolution of neuronal wiring receptors and ligands. Cortés E, Pak JS, Özkan E. Dev Dyn 252 27-60 (2023)

Articles citing this publication (12)

  1. Molecular mechanisms regulating axon responsiveness at the midline. Gorla M, Bashaw GJ. Dev Biol 466 12-21 (2020)
  2. Minimal structural elements required for midline repulsive signaling and regulation of Drosophila Robo1. Brown HE, Evans TA. PLoS One 15 e0241150 (2020)
  3. Robo functions as an attractive cue for glial migration through SYG-1/Neph. Qu Z, Zhang A, Yan D. Elife 9 e57921 (2020)
  4. Structure of the class C orphan GPCR GPR158 in complex with RGS7-Gβ5. Jeong E, Kim Y, Jeong J, Cho Y. Nat Commun 12 6805 (2021)
  5. Alterations in Self-Aggregating Neuropeptides in Cerebrospinal Fluid of Patients with Parkinsonian Disorders. Zhu S, Bäckström D, Forsgren L, Trupp M. J Parkinsons Dis 12 1169-1189 (2022)
  6. Robo2 Receptor Gates the Anatomical Divergence of Neurons Derived From a Common Precursor Origin. Wurmser M, Muppavarapu M, Tait CM, Laumonnerie C, González-Castrillón LM, Wilson SI. Front Cell Dev Biol 9 668175 (2021)
  7. Identification of gene targets of developmental neurotoxicity focusing on DNA hypermethylation involved in irreversible disruption of hippocampal neurogenesis in rats. Kikuchi S, Takahashi Y, Ojiro R, Takashima K, Okano H, Tang Q, Woo GH, Yoshida T, Shibutani M. J Appl Toxicol 41 1021-1037 (2021)
  8. Neural Epidermal Growth Factor-Like Like Protein 2 Is Expressed in Human Oligodendroglial Cell Types. Shaker MR, Kahtan A, Prasad R, Lee JH, Pietrogrande G, Leeson HC, Sun W, Wolvetang EJ, Slonchak A. Front Cell Dev Biol 10 803061 (2022)
  9. Transcriptional Regulatory Role of NELL2 in Preproenkephalin Gene Expression. Ha CM, Kim DH, Lee TH, Kim HR, Choi J, Kim Y, Kang D, Park JW, Ojeda SR, Jeong JK, Lee BJ. Mol Cells 45 537-549 (2022)
  10. PCDH7 as the key gene related to the co-occurrence of sarcopenia and osteoporosis. Liu M, Wang Y, Shi W, Yang C, Wang Q, Chen J, Li J, Chen B, Sun G. Front Genet 14 1163162 (2023)
  11. Function of cell adhesion molecules in differentiation of ray sensory neurons in C. elegans. Sakai N, Sun P, Kim B, Emmons SW. G3 (Bethesda) 13 jkac338 (2023)
  12. Positioning-dependent bidirectional NELL2 signaling in the brain. Lee BJ, Jeong JK. Front Endocrinol (Lausanne) 13 1049595 (2022)


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