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

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.

Authors:
ORCiD logo [1]; ORCiD logo [2];  [1];  [2];  [3]; ORCiD logo [2]; ORCiD logo [1]
  1. Univ. of Chicago, IL (United States). Grossman Inst. for Neuroscience, Quantitative Biology and Human Behavior
  2. Brown Univ., Providence, RI (United States); Robert J. and Nancy D. Carney Inst. for Brain Science, Providence, RI (United States)
  3. Univ. of Chicago, IL (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); National Institute of General Medical Sciences (NIGMS); USDOE Office of Science (SC)
OSTI Identifier:
1608059
Grant/Contract Number:  
AC02-06CH11357; T32 GM077995; R01 NS097161; R01 MH114102; RI-INBRE P20 GM103430; R01 NS095908; S10 RR029205; 1S10OD012289-01A1; 9 P41 GM103622; 1S10OD018090-01
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 11; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Pak, Joseph S., DeLoughery, Zachary J., Wang, Jing, Acharya, Nischal, Park, Yeonwoo, Jaworski, Alexander, and Özkan, Engin. NELL2-Robo3 complex structure reveals mechanisms of receptor activation for axon guidance. United States: N. p., 2020. Web. doi:10.1038/s41467-020-15211-1.
Pak, Joseph S., DeLoughery, Zachary J., Wang, Jing, Acharya, Nischal, Park, Yeonwoo, Jaworski, Alexander, & Özkan, Engin. NELL2-Robo3 complex structure reveals mechanisms of receptor activation for axon guidance. United States. doi:https://doi.org/10.1038/s41467-020-15211-1
Pak, Joseph S., DeLoughery, Zachary J., Wang, Jing, Acharya, Nischal, Park, Yeonwoo, Jaworski, Alexander, and Özkan, Engin. Fri . "NELL2-Robo3 complex structure reveals mechanisms of receptor activation for axon guidance". United States. doi:https://doi.org/10.1038/s41467-020-15211-1. https://www.osti.gov/servlets/purl/1608059.
@article{osti_1608059,
title = {NELL2-Robo3 complex structure reveals mechanisms of receptor activation for axon guidance},
author = {Pak, Joseph S. and DeLoughery, Zachary J. and Wang, Jing and Acharya, Nischal and Park, Yeonwoo and Jaworski, Alexander and Özkan, Engin},
abstractNote = {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.},
doi = {10.1038/s41467-020-15211-1},
journal = {Nature Communications},
number = 1,
volume = 11,
place = {United States},
year = {2020},
month = {3}
}

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