Background: The molecular components in synapses that are essential to the life cycle of synaptic vesicles are well characterized. Nonetheless, many aspects of synaptic processes, in particular how they relate to complex behaviour, remain elusive. The genomes of flies, mosquitoes, the honeybee and the beetle are now fully sequenced and span an evolutionary breadth of about 350 million years; this provides a unique opportunity to conduct a comparative genomics study of the synapse. Results: We compiled a list of 120 gene prototypes that comprise the core of presynaptic structures in insects. Insects lack several scaffolding proteins in the active zone, such as bassoon and piccollo, and the most abundant protein in the mammalian synaptic vesicle, namely synaptophysin. The pattern of evolution of synaptic protein complexes is analyzed. According to this analysis, the components of presynaptic complexes as well as proteins that take part in organelle biogenesis are tightly coordinated. Most synaptic proteins are involved in rich protein interaction networks. Overall, the number of interacting proteins and the degrees of sequence conservation between human and insects are closely correlated. Such a correlation holds for exocytotic but not for endocytotic proteins. Conclusion: This comparative study of human with insects sheds light on the composition and assembly of protein complexes in the synapse. Specifically, the nature of the protein interaction graphs differentiate exocytotic from endocytotic proteins and suggest unique evolutionary constraints for each set. General principles in the design of proteins of the presynaptic site can be inferred from a comparative study of human and insect genomes.
Bibliographical noteFunding Information:
We are grateful to Menachem Fromer for critical reading, advice, and support. NM received a fellowship from the SCCB, the Sudarsky Center for Computational Biology. This study was supported by the EU DIAMONDS consortium of the Framework 6 and the Israeli Horvitz Foundation.