Posttranslational modifications of neuroligins regulate neuronal and glial signaling

Abstract

This review covers the dynamic regulation of neuroligin isoforms, focusing on posttranslational events including phosphorylation, glycosylation and activity-dependent cleavage. There is a growing literature on how phosphorylation confers an isoform-specific level of modulation affecting a variety of protein interactions. In addition, recent studies describe activity-dependent proteolytic cleavage of neuroligins, revealing a broader role for neuroligins than just synaptic 'glue'. Interesting new research implicates the cleaved extracellular fragments of neuroligins in promoting glioma. These reports on cell signaling mediated by the cleavage products of neuroligins suggest novel and important roles for neuroligins in neuro-glial signaling.

Figure 1. Posttranslational modification sites in the juxtamembrane stalk and cytoplasmic regions of neuroligin isoforms

A cartoon of the structure of a neuroligin is depicted on the left and an alignment of the juxtamembrane and cytoplasmic regions of mouse neuroligin isoforms are aligned on the right. The residues that are phosphorylated are indicated with a red box. The residue identified in an autism patient is shaded in black. A reported ubiquitination site (light green) and methylation site (orange) are indicated. Residues that were identified in human neuroligins are marked at the analogous residues within the mouse neuroligin sequence. The divergent juxtamembrane stalk region is highlighted in green, with critical cleavage residues highlighted in yellow. An asterisk (*) indicates conserved amino acid residues between neuroligin isoforms; a colon (:) indicates conservation between amino acids with strongly similar properties; and, a period (.) indicates conservation between weakly similar amino acids.

Figure 2. Regulation of neuroligins by posttranslational modifications

Neuroligins are single transmembrane proteins that form homo- and hetero- dimers. A schematic drawing of neuroligins is shown as a monomer for convenience. The transmembrane regions are depicted as a dark blue rectangle. The B splicing site (light blue), phosphorylation sites (black circles), glycosylation sites (green diamonds), autism mutation sites (red), ubiquitination sites (purple) and methylation sites (yellow) are indicated with a legend shown in the box. Regulatory roles of each posttranslational modification on neuroligins are described in the text boxes if functional studies have been reported for the relevant site. The amino acid residues are numbered as in the reference paper.

Figure 3. Activity-dependent cleavage of neuroligins

(A) Activity triggers the cleavage of the NLGN1-NTF, mediated by MMP9 and/or ADAM10. The resultant free NLGN1-CTF displays autonomous functional roles similar to full-length NLGN1, increasing spine number and potentiating excitatory neurotransmission. NLGN1-CTF is subsequently degraded by γ-secretase. (B) Activity triggers cleavage of NLGN3, releasing the soluble NLGN3-NTF, which mediates activity-dependent glioma growth. (C) Expression of neuroligin isoforms in glial cells. Astrocyte-derived hevin acts as a linker protein, bridging the interaction of NLGN1B and NRXN1α.