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Family of neural wiring receptors in bilaterians defined by phylogenetic, biochemical, and structural evidence

Cheng, Shouqiang and Park, Yeonwoo and Kurleto, Justyna D. and Jeon, Mili and Zinn, Kai and Thornton, Joseph W. and Özkan, Engin (2019) Family of neural wiring receptors in bilaterians defined by phylogenetic, biochemical, and structural evidence. Proceedings of the National Academy of Sciences of the United States of America, 116 (20). pp. 9837-9842. ISSN 0027-8424. PMCID PMC6525511. https://resolver.caltech.edu/CaltechAUTHORS:20181107-102736267

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Abstract

The evolution of complex nervous systems was accompanied by the expansion of numerous protein families, including cell-adhesion molecules, surface receptors, and their ligands. These proteins mediate axonal guidance, synapse targeting, and other neuronal wiring-related functions. Recently, 32 interacting cell surface proteins belonging to two newly defined families of the Ig superfamily (IgSF) in fruit flies were discovered to label different subsets of neurons in the brain and ventral nerve cord. They have been shown to be involved in synaptic targeting and morphogenesis, retrograde signaling, and neuronal survival. Here, we show that these proteins, Dprs and DIPs, are members of a widely distributed family of two- and three-Ig domain molecules with neuronal wiring functions, which we refer to as Wirins. Beginning from a single ancestral Wirin gene in the last common ancestor of Bilateria, numerous gene duplications produced the heterophilic Dprs and DIPs in protostomes, along with two other subfamilies that diversified independently across protostome phyla. In deuterostomes, the ancestral Wirin evolved into the IgLON subfamily of neuronal receptors. We show that IgLONs interact with each other and that their complexes can be broken by mutations designed using homology models based on Dpr and DIP structures. The nematode orthologs ZIG-8 and RIG-5 also form heterophilic and homophilic complexes, and crystal structures reveal numerous apparently ancestral features shared with Dpr-DIP complexes. The evolutionary, biochemical, and structural relationships we demonstrate here provide insights into neural development and the rise of the metazoan nervous system.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1073/pnas.1818631116DOIArticle
https://www.pnas.org/content/suppl/2019/05/01/1818631116.DCSupplementalPublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525511PubMed CentralArticle
https://doi.org/10.1101/462036DOIDiscussion Paper
ORCID:
AuthorORCID
Cheng, Shouqiang0000-0001-6417-2635
Zinn, Kai0000-0002-6706-5605
Özkan, Engin0000-0002-0263-6729
Alternate Title:A new family of neural wiring receptors across bilaterians defined by phylogenetic, biochemical and structural evidence
Additional Information:© 2019 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). Edited by Rachelle Gaudet, Harvard University, Cambridge, MA, and accepted by Editorial Board Member Jeremy Nathans April 8, 2019 (received for review November 5, 2018). We thank Yeonhee J. Park and Elana Baltrusaitis for technical help and Paschalis Kratsios and J.W.T.’s laboratory for discussions and guidance. This work was supported in part by NIH Grants R01 NS097161 (to E.Ö.), R01 GM121931 (to J.W.T.), R37 NS028182 (to K.Z.), and R01 NS096509 (to K.Z.) and a Klingenstein-Simons Fellowship Award in the Neurosciences (to E.Ö.). Use of the Stanford Synchrotron Radiation Lightsource (SSRL), SLAC National Accelerator Laboratory is supported by the US Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences under Contract DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the NIH, National Institute of General Medical Sciences (NIGMS) (including Grant P41GM103393). This work is also based upon research conducted at the Northeastern Collaborative Access Team beamlines funded by NIGMS from the NIH (Grant P30 GM124165) at the Advanced Photon Source, a US DOE Office of Science user facility operated by the Argonne National Laboratory under Contract DE-AC02-06CH11357. The Pilatus 6M detector on 24-ID-C beamline is funded by NIH Office of Research Infrastructure High-End Instrumentation Grant S10 RR029205. Author contributions: S.C., Y.P., J.D.K., M.J., K.Z., J.W.T., and E.Ö. designed research; S.C., Y.P., J.D.K., and M.J. performed research; S.C., Y.P., J.D.K., K.Z., J.W.T., and E.Ö. analyzed data; and S.C., Y.P., K.Z., J.W.T., and E.Ö. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. R.G. is a guest editor invited by the Editorial Board. Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.wwpdb.org (PDB ID codes 6ON6, 6ON9, and 6ONB). This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1818631116/-/DCSupplemental.
Funders:
Funding AgencyGrant Number
NIHR01 NS097161
NIHR01 GM121931
NIHR37 NS028182
NIHR01 NS096509
Klingenstein-Simons FellowshipUNSPECIFIED
Department of Energy (DOE)DE-AC02-76SF00515
NIHP41GM103393
NIHP30 GM124165
Department of Energy (DOE)DE-AC02-06CH11357
NIHS10 RR029205
Subject Keywords:immunoglobulin superfamily; molecular evolution; nervous system; IgLON; Dpr-DIP family
Issue or Number:20
PubMed Central ID:PMC6525511
Record Number:CaltechAUTHORS:20181107-102736267
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20181107-102736267
Official Citation:Family of neural wiring receptors in bilaterians defined by phylogenetic, biochemical, and structural evidence. Shouqiang Cheng, Yeonwoo Park, Justyna D. Kurleto, Mili Jeon, Kai Zinn, Joseph W. Thornton, Engin Özkan. Proceedings of the National Academy of Sciences May 2019, 116 (20) 9837-9842; DOI: 10.1073/pnas.1818631116
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90704
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:07 Nov 2018 19:22
Last Modified:03 Oct 2019 20:27

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