Construction and analysis of protein-protein interaction network associated with human sperm-egg interaction

Abstract

Complete elucidation of sperm-egg interaction at molecular level is one of the unresolved challenges in sexual reproduction studies, and the understanding the molecular mechanism is crucial in overcoming difficulties in infertility and unsuccessful in-vitro fertilization. Numerous molecular interactions in the form of protein-protein interactions mediate the sperm-egg membrane interaction process. Due to the various limitations of materials and difficulties in analyzing vivo membrane protein-protein interaction, many efforts have failed to comprehensively consider the interaction mechanism at molecular level which mediates sperm-egg membrane interaction. The main purpose of this study was to identify the possible protein interaction in human sperm-egg interaction using the protein-protein interaction network approach. Datasets from varying databases containing information on membrane-associated proteins in sperm-egg binding and fusion process have been utilized to construct human sperm-egg interaction network using Cytoscape Software. The analyzing network represented new interactions in binding and fusion of sperm to egg. CD151 and CD9 in human oocyte had interaction with CD49 in sperm, and CD49 and ITGA4 in sperm interacted with CD63 and CD81 respectively in the oocyte. These results showed that the different integrins in sperm may be involved in human sperm-egg interaction. It also revealed novel interactions between acrosomal proteins in sperm and membrane proteins in oocyte. The Fn1, PDIA6 and ARSA from acrosome content of sperm have been shown to interact with ITGA9, IGSF8 and BMPR2 in oocyte, respectively. Topological analysis of the sperm-egg interaction network identified ITGB1, FN1, EGFR, ITGA3, ITGAV, ITGB3 and COL1A1 as putative drug targets to future study on sperm-egg interaction disorder. Using functional analysis of the network by ClueGo and ClueGo Pedia (two Cytoscape Plugins), the major molecular functions in sperm-egg interaction protein network was identified. The Interleukin-4 receptor activity, receptor signaling protein tyrosine kinase activity, manganese ion transmembrane transport activity were identified as the major molecular function group in sperm-egg interaction protein network. The disease association analysis using Database for Annotation Visualization and Integrated Discovery (DAVID) analysis represented the associated diseases with sperm-egg interaction disorder and indicated that spermegg interaction defects possess significant association with diseases such as cardiovascular, hematological and breast cancer. The Ingenuity Pathway Analysis (IPA) of the putative drug targets showed that the drugs ocriplasmin (Jetrea©), gefitinib (Iressa©), erlotinib hydrochloride (Tarceva©), clingitide, cetuximab (Erbitux©) and panitumumab (Vectibix©) are possible candidates for efficacy testing for the treatment of infertility cases. In conclusion, the result of this study has generated new knowledge regarding sperm-egg interaction that is for future proteomic studies.