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A Proteomic Screen of Neuronal Cell-Surface Molecules Reveals IgLONs as Structurally Conserved Interaction Modules at the Synapse

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posted on 04.08.2022, 22:22 authored by FM Ranaivoson, LS Turk, S Ozgul, S Kakehi, S von Daake, N Lopez, L Trobiani, A De Jaco, N Denissova, B Demeler, E Özkan, GT Montelione, Davide ComolettiDavide Comoletti
In the developing brain, cell-surface proteins play crucial roles, but their protein-protein interaction network remains largely unknown. A proteomic screen identified 200 interactions, 89 of which were not previously published. Among these interactions, we find that the IgLONs, a family of five cell-surface neuronal proteins implicated in various human disorders, interact as homo- and heterodimers. We reveal their interaction patterns and report the dimeric crystal structures of Neurotrimin (NTRI), IgLON5, and the neuronal growth regulator 1 (NEGR1)/IgLON5 complex. We show that IgLONs maintain an extended conformation and that their dimerization occurs through the first Ig domain of each monomer and is Ca2+ independent. Cell aggregation shows that NTRI and NEGR1 homo- and heterodimerize in trans. Taken together, we report 89 unpublished cell-surface ligand-receptor pairs and describe structural models of trans interactions of IgLONs, showing that their structures are compatible with a model of interaction across the synaptic cleft. Many aspects of synapse formation, specification, and maturation rely on interactions among a rich repertoire of cell-surface glycoproteins with adhesive and repulsive properties. Although the identity of these proteins is known, their network of interactions remains largely untapped. Ranaivoson et al. have identified a number of protein-protein interactions and have determined the structures of three members of the IgLONs, a family of five proteins of the immunoglobulin superfamily that has recently been implicated in a wide range of human disease.

Funding

Collaborative Research: Structure and Function of Reelin in Brain Development | Funder: RUTGERS UNIVERSITY | Grant ID: 1755189

History

Preferred citation

Ranaivoson, F. M., Turk, L. S., Ozgul, S., Kakehi, S., von Daake, S., Lopez, N., Trobiani, L., De Jaco, A., Denissova, N., Demeler, B., Özkan, E., Montelione, G. T. & Comoletti, D. (2019). A Proteomic Screen of Neuronal Cell-Surface Molecules Reveals IgLONs as Structurally Conserved Interaction Modules at the Synapse. Structure, 27(6), 893-906.e9. https://doi.org/10.1016/j.str.2019.03.004

Journal title

Structure

Volume

27

Issue

6

Publication date

04/06/2019

Pagination

893-906.e9

Publisher

Elsevier BV

Publication status

Published

Online publication date

04/04/2019

ISSN

0969-2126

eISSN

1878-4186

Language

en