Structural Plasticity of Neurexin 1α: Implications for its Role as Synaptic Organizer

Jianfang Liu, Anurag Misra, M. V.V.V.Sekhar Reddy, Mark Andrew White, Gang Ren, Gabby Rudenko

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

α-Neurexins are synaptic organizing molecules implicated in neuropsychiatric disorders. They bind and arrange an array of different partners in the synaptic cleft. The extracellular region of neurexin 1α (n1α) contains six LNS domains (L1–L6) interspersed by three Egf-like repeats. N1α must encode highly evolved structure–function relationships in order to fit into the narrow confines of the synaptic cleft, and also recruit its large, membrane-bound partners. Internal molecular flexibility could provide a solution; however, it is challenging to delineate because currently no structural methods permit high-resolution structure determination of large, flexible, multi-domain protein molecules. To investigate the structural plasticity of n1α in particular the conformation of domains that carry validated binding sites for different protein partners, we used a panel of structural techniques. Individual particle electron tomography revealed that the N-terminally and C-terminally tethered domains, L1 and L6, have a surprisingly limited range of conformational freedom with respect to the linear central core containing L2 through L5. A 2.8-Å crystal structure revealed an unexpected arrangement of the L2 and L3 domains. Small-angle X-ray scattering and electron tomography indicated that incorporation of the alternative splice insert SS6 relieves the restricted conformational freedom between L5 and L6, suggesting that SS6 may work as a molecular toggle. The architecture of n1α thus encodes a combination of rigid and flexibly tethered domains that are uniquely poised to work together to promote its organizing function in the synaptic cleft, and may permit allosterically regulated and/or concerted protein partner binding.

Original languageEnglish (US)
Pages (from-to)4325-4343
Number of pages19
JournalJournal of Molecular Biology
Volume430
Issue number21
DOIs
StatePublished - Oct 19 2018

Keywords

  • adhesion
  • neuropsychiatric disorders
  • protein structure
  • single-molecule 3D density map
  • synapse

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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