Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions

Area of Science:

• Neuroscience
• Structural Biology
• Molecular Biology

Background:

• Synaptic adhesion molecules, neuroligins and neurexins, are critical for neuronal circuit formation and maturation.
• The neuroligin-neurexin interaction is calcium-dependent and influenced by alternative splicing.

Purpose of the Study:

• To determine the high-resolution structure of the neuroligin-1 (NL1) cholinesterase-like domain bound to the neurexin-1beta (NX1beta) LNS domain.
• To elucidate the structural mechanisms underlying neuroligin-neurexin complex formation and regulation by alternative splicing.

Main Methods:

• X-ray crystallography to obtain the structure of the NL1-NX1beta complex at 2.4 A resolution.
• Thermodynamic analysis to investigate the role of alternative splicing at splicing site B of NL1.
• Structural mapping of neuroligin mutations associated with autism spectrum disorder.

Main Results:

• The structure reveals a Ca2+-mediated, hydrophilic interface between NL1 and NX1beta, suggesting a mechanism for modulation by splicing and other factors.
• Thermodynamic data indicate that splicing site B of NL1 influences the complex through a salt bridge at the interface.
• Most autism-associated neuroligin mutations were found to be structurally destabilizing, implying impaired biosynthesis and processing.

Conclusions:

• The detailed structure provides insights into the regulation of synaptic adhesion by alternative splicing and Ca2+.
• Deficient neuroligin biosynthesis and processing due to destabilizing mutations may be a common mechanism underlying autism spectrum disorder.