Structural basis for variant-specific neuroligin-binding by α-neurexin

PLoS One. 2011 Apr 28;6(4):e19411. doi: 10.1371/journal.pone.0019411.

Abstract

Neurexins (Nrxs) are presynaptic membrane proteins with a single membrane-spanning domain that mediate asymmetric trans-synaptic cell adhesion by binding to their postsynaptic receptor neuroligins. α-Nrx has a large extracellular region comprised of multiple copies of laminin, neurexin, sex-hormone-binding globulin (LNS) domains and epidermal growth factor (EGF) modules, while that of β-Nrx has but a single LNS domain. It has long been known that the larger α-Nrx and the shorter β-Nrx show distinct binding behaviors toward different isoforms/variants of neuroligins, although the underlying mechanism has yet to be elucidated. Here, we describe the crystal structure of a fragment corresponding to the C-terminal one-third of the Nrx1α ectodomain, consisting of LNS5-EGF3-LNS6. The 2.3 Å-resolution structure revealed the presence of a domain configuration that was rigidified by inter-domain contacts, as opposed to the more common flexible "beads-on-a-string" arrangement. Although the neuroligin-binding site on the LNS6 domain was completely exposed, the location of the α-Nrx specific LNS5-EGF3 segment proved incompatible with the loop segment inserted in the B+ neuroligin variant, which explains the variant-specific neuroligin recognition capability observed in α-Nrx. This, combined with a low-resolution molecular envelope obtained by a single particle reconstruction performed on negatively stained full-length Nrx1α sample, allowed us to derive a structural model of the α-Nrx ectodomain. This model will help us understand not only how the large α-Nrx ectodomain is accommodated in the synaptic cleft, but also how the trans-synaptic adhesion mediated by α- and β-Nrxs could differentially affect synaptic structure and function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cattle
  • Cell Adhesion Molecules, Neuronal / metabolism*
  • Extracellular Matrix / metabolism
  • Glycoproteins / chemistry*
  • Glycoproteins / metabolism*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Neuropeptides / chemistry*
  • Neuropeptides / metabolism*
  • Protein Binding
  • Protein Isoforms / metabolism
  • Protein Structure, Tertiary
  • Substrate Specificity
  • Synapses / metabolism

Substances

  • Cell Adhesion Molecules, Neuronal
  • Glycoproteins
  • Neuropeptides
  • Protein Isoforms
  • neurexophilin
  • neuroligin 1

Associated data

  • PDB/3ASI