Figure 1.

Molecular hand-clasp interaction between NetrinGs and cognate NGLs. (A) NetrinG1 expressed by specific populations of axons interacts with and aggregates NGL1 present on target dendrites, whereas axonal netrinG2 interacts with and aggregates dendritic NGL2. (B) Illustration of the domain architecture of netrinG and NGL proteins. Domains VI and V of netrinGs are homologous to domains VI and V found in laminins. Domain C terminates in a GPI anchor that links the NetrinG to the plasma membrane. Substantial sequence diversity is generated in domain V through alternative mRNA splicing. Single nucleotide polymorphisms (SNPs) in human netrinG1 and netrinG2 genes have been identified, some of which are associated with Schizophrenia, but how these influence expression or NGL binding remains to be determined. NGLs are single pass transmembrane LRR proteins composed of a series of extracellular leucine-rich repeat domains followed by an Ig domain, a transmembrane sequence, and an intracellular PDZ-binding motif. (C) In this issue of The EMBO Journal, Seiradake et al report that the concave surface of the NGL LRR domain cradles three loops contained within the netrinG LAM domain, described as a ‘hand-clasp’ model of binding.