Designer molecules of the synaptic organizer MDGA1 reveal 3D conformational control of biological function.

Autor:	Lee H; Deptartment of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX, USA., Chofflet N; Synapse Development and Plasticity Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, Quebec, Canada; Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada., Liu J; The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Fan S; Deptartment of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX, USA., Lu Z; The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Resua Rojas M; Synapse Development and Plasticity Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, Quebec, Canada., Penndorf P; Synapse Development and Plasticity Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, Quebec, Canada., Bailey AO; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA., Russell WK; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA., Machius M; Deptartment of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX, USA., Ren G; The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. Electronic address: gren@lbl.gov., Takahashi H; Synapse Development and Plasticity Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, Quebec, Canada; Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada; Department of Medicine, Université de Montréal, Montréal, Quebec, Canada; Division of Experimental Medicine, McGill University, Montréal, Quebec, Canada. Electronic address: Hideto.Takahashi@ircm.qc.ca., Rudenko G; Deptartment of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX, USA. Electronic address: garudenk@utmb.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2023 Apr; Vol. 299 (4), pp. 104586. Date of Electronic Publication: 2023 Mar 07.
DOI:	10.1016/j.jbc.2023.104586
Abstrakt:	MDGAs (MAM domain-containing glycosylphosphatidylinositol anchors) are synaptic cell surface molecules that regulate the formation of trans-synaptic bridges between neurexins (NRXNs) and neuroligins (NLGNs), which promote synaptic development. Mutations in MDGAs are implicated in various neuropsychiatric diseases. MDGAs bind NLGNs in cis on the postsynaptic membrane and physically block NLGNs from binding to NRXNs. In crystal structures, the six immunoglobulin (Ig) and single fibronectin III domains of MDGA1 reveal a striking compact, triangular shape, both alone and in complex with NLGNs. Whether this unusual domain arrangement is required for biological function or other arrangements occur with different functional outcomes is unknown. Here, we show that WT MDGA1 can adopt both compact and extended 3D conformations that bind NLGN2. Designer mutants targeting strategic molecular elbows in MDGA1 alter the distribution of 3D conformations while leaving the binding affinity between soluble ectodomains of MDGA1 and NLGN2 intact. In contrast, in a cellular context, these mutants result in unique combinations of functional consequences, including altered binding to NLGN2, decreased capacity to conceal NLGN2 from NRXN1β, and/or suppressed NLGN2-mediated inhibitory presynaptic differentiation, despite the mutations being located far from the MDGA1-NLGN2 interaction site. Thus, the 3D conformation of the entire MDGA1 ectodomain appears critical for its function, and its NLGN-binding site on Ig1-Ig2 is not independent of the rest of the molecule. As a result, global 3D conformational changes to the MDGA1 ectodomain via strategic elbows may form a molecular mechanism to regulate MDGA1 action within the synaptic cleft. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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