The human postsynaptic density shares conserved elements with proteomes of unicellular eukaryotes and prokaryotes

Abstract

The animal nervous system processes information from the environment and mediates learning and memory using molecular signaling pathways in the postsynaptic terminal of synapses. Postsynaptic neurotransmitter receptors assemble to form multiprotein complexes that drive signal transduction pathways to downstream cell biological processes. Studies of mouse and Drosophila postsynaptic proteins have identified key roles in synaptic physiology and behavior for a wide range of proteins including receptors, scaffolds, enzymes, structural, translational, and transcriptional regulators. Comparative proteomic and genomic studies identified components of the postsynaptic proteome conserved in eukaryotes and early metazoans. We extend these studies, and examine the conservation of genes and domains found in the human postsynaptic density with those across the three superkingdoms, archaeal, bacteria, and eukaryota. A conserved set of proteins essential for basic cellular functions were conserved across the three superkingdoms, whereas synaptic structural and many signaling molecules were specific to the eukaryote lineage. Genes involved with metabolism and environmental signaling in Escherichia coli including the chemotactic and ArcAB Two-Component signal transduction systems shared homologous genes in the mammalian postsynaptic proteome. These data suggest conservation between prokaryotes and mammalian synapses of signaling mechanisms from receptors to transcriptional responses, a process essential to learning and memory in vertebrates. A number of human postsynaptic proteins with homologs in prokaryotes are mutated in human genetic diseases with nervous system pathology. These data also indicate that structural and signaling proteins characteristic of postsynaptic complexes arose in the eukaryotic lineage and rapidly expanded following the emergence of the metazoa, and provide an insight into the early evolution of synaptic mechanisms and conserved mechanisms of learning and memory.

Keywords: brain; comparative genomics; phylogenetics; proteome; synapse.

Figure 1

Phylogeny of compared species. The generalized phylogeny of the three superkingdoms studied, adapted from (Woese et al., 1990). Numbers in parentheses relate to full species names and taxonomy given in Supplemental Table S1. LECA, last eukaryotic common ancestor. LUCA, last universal common ancestor.

Figure 2

Numbers of hPSD homologs in phylogenetic groups. (A) Histogram of homologs identified in each species tested as a percent of the human PSD dataset (blue archaea, red bacteria, green S. cerevisiae). (B) i Comparison of number of identified hPSD proteome homologs across three superkingdoms, ii subset of i highlighting number of identified hPSD proteome homologs identified in at least a single bacterial and archaeal species, iii subset of i highlighting number of identified hPSD proteome homologs in bacteria, iv subset of i highlighting number of identified hPSD proteome homologs in archaea. In all sections, percentage of 1429 hPSD genes tested are shown in parentheses.

Figure 3

Conservation of hPSD protein types. Relative composition of identified protosynapse compared to human postsynaptic density. Mean bacterial or archaeal percentage of identified homologs were compared to the percent of human genes in a protein supercategory.

Figure 4

Gene ontology (GO) expansions and innovations associated with conserved protein domains. Protein domains conserved between human and tested species were used to determine associated GO terms (see Materials and Methods). GO terms shown in black are associated with protein domains conserved in eukaryote, archaeal, and bacterial species. GO terms shown in blue are associated with Pfam domains not shared between humans and any archaeal or bacterial species tested.