Structure-function relationships of the α/β-hydrolase fold domain of neuroligin: A comparison with acetylcholinesterase

The neuroligins are postsynaptic cell adhesion proteins whose extracellular domain belongs to the alpha/beta-hydrolase fold family of proteins, a family characterized through the enzyme acetylcholinesterase (AChE) and other enzymes with various substrate specificities. Neuroligin associations with the pre-synaptic neurexins participate in synapse maturation and maintenance. Alternative splicing of the neuroligin and neurexin genes results in multiple isoforms and presumably regulation of activity, while mutations appear to be associated with autism spectrum disorders. The crystal structures of the extracellular, cell adhesion domain of three neuroligins (NL1, NL2 and NL4) revealed features that distinguish the neuroligins from their enzyme relatives and could not be predicted by homology modelling from an AChE template. The structures of NU and NL4 bound with a soluble beta-neurexin domain (Nrx beta 1) revealed the precise position and orientation of the bound Nrx beta 1 and the Ca2+-dependent interaction network at the complex interface. Herein we present an overview of the unbound and Nrx beta 1-bound neuroligin structures and compare them with structures of AChEs with and without a bound fasciculin partner. This study exemplifies how an alpha/beta-hydrolase fold domain tailored for catalysis varies to acquire adhesion properties, and defines three surface regions with distinctive locations and properties for homologous or heterologous partner association. (C) 2010 Elsevier Ireland Ltd. All rights reserved.