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

Hubert Lee, Nicolas Chofflet, Jianfang Liu, Shanghua Fan, Zhuoyang Lu, Martin Resua Rojas, Patrick Penndorf, Aaron O. Bailey, William K. Russell, Mischa Machius, Gang Ren, Hideto Takahashi, Gabby Rudenko

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number104586
JournalJournal of Biological Chemistry
Volume299
Issue number4
DOIs
StatePublished - Apr 2023
Externally publishedYes

Keywords

  • MDGAs
  • adhesion molecules
  • conformational change
  • neurexins
  • neuroligins
  • neuropsychiatric disease
  • protein structure
  • synaptic organizers

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Designer molecules of the synaptic organizer MDGA1 reveal 3D conformational control of biological function'. Together they form a unique fingerprint.

Cite this