Using Protein Structural Analysis To Predict The Impact Of Single Nucleotide Variants On The Function Of Neurexin And Neuroligin

The synapse is a highly specialized and dynamic structure,which is involved in regulating neurotransmission.Nerve cell adhesion molecule is a kind of transmembrane protein that mediates the interaction between cells and cells,cells and extracellular matrix,and plays a role in cell recognition,metastasis,and transmembrane signal transduction.Among nerve cell adhesion molecules,Neurexins and Neuroligins have been focused due to the relation with autism and other neuropsychiatric diseases.High-throughput sequencing has been stimulating the development of clinical genome,microgenome and other research fields.The previous research discovered numerous variants in Neurexins and Neuroligins reported in neurodevelopmental disorders by genomic sequencing.However,structural variants in synaptic molecules caused by genome variants still prevent us from understanding the molecular mechanism of diseases.In order to conduct a comprehensive risk assessment of the known Neurexin and Neuroligin gene mutations by protein structure analysis.First,we explored the distribution characteristics of gene mutations in Neurexin and Neuroligin through systematic analysis and point mutation localization.Subsequently,the impact of these mutations were analyzed by four mutation prediction tools.Finally,residue scanning calculation,in combination with existing risk assessment tools,is applied to focus on candidate missense mutations,and analyze the structural changes of Neurexin/Neuroligin complexes.We proposed that five candidate missense mutations in Nlgns can reduce the stability of Nlgns and even prevent the formation of Nrxn/Nlgn complexes,namely R87 W,R204H,R437 H,R437C and R583 W.In addition,we found that the affinity of the amino acid substitution(Leu593Phe)(??G(affinity))changes the affinity of the Nlgn dimer.In a summary,we have identified important potential pathological mutations that provide clues to biomarkers and proposed candidate amino acid substitutions for early diagnosis of neurodevelopmental disorders.