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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 Taken together, we report 89 unpublished cell-surface ligand-receptor pairs and describe structural models of trans interactions of IgLONs, showing that their structures are compatible with a model of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.


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


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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

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Elsevier BV

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