Abstract
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 (NRXNs) and Neuroligins (NLGNs) have been focused due to the relation with autism and other neuropsychiatric diseases. The previous research discovered numerous variants in NRXNs and NLGNs 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. Thus, we sought to conduct a comprehensive risk assessment of the known NRXN and NLGN gene variants by protein structure analysis. In this study, we analyzed the structural properties of the NRXN/NLGN complex by calculating free energy in residue scanning, in combination with existing risk evaluation tools to focus on candidate missense mutations. Our calculations show that five candidate missense mutations in NLGNs can reduce the stability of NLGNs and even prevent the formation of NRXN/NLGN complexes, namely R87W, R204H, R437H, R437C and R583W. In addition, we found that the affinity of the amino acid substitution (Leu593Phe) (ΔΔG(affinity)) changes the affinity of the NLGN dimer. Overall, we have identified important potential pathological variants that provide clues to biomarkers.
Communicated by Ramaswamy H. Sarma
Acknowledgements
We are thankful to our colleagues in our lab for their valuable suggestions. We thank the Big Data Computing Center of Southeast University for providing the facility support on the numerical calculations in this paper.
Authors’ contributions
JL and WX conceived and supervised this work. KYX and YYH conducted data collection and data analysis. SLG, CW, RK assisted the data analysis. KYX drafted the manuscript. JL, YYH, RK and WX modified the manuscript. All authors read and approved the manuscript.
Data availability statement
All sequences involved in this manuscript are available in Genbank (https://www.ncbi.nlm.nih.gov/genbank/) and UniprotKB (https://www.uniprot.org/). Structure information could acquire from RCSB PDB (https://www.rcsb.org/). The point mutation information is available in HGMD professional (http://portal.biobaseinternational.com/hgmd/pro/search_gene.php). HGMD professional is a commercial database and the homepage is http://www.hgmd.cf.ac.uk/ac/index.php.
Disclosure statement
The authors declare that they have no competing interests.