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Ancestry and evolution of a secretory pathway serpin.
BACKGROUND: The serpin (serine protease inhibitor) superfamily constitutes a class of functionally highly diverse proteins usually encompassing several dozens of paralogs in mammals. Though phylogenetic classification of vertebrate serpins into six groups based on gene organisation is well established, the evolutionary roots beyond the fish/tetrapod split are unresolved. The aim of this study was to elucidate the phylogenetic relationships of serpins involved in surveying the secretory pathway routes against uncontrolled proteolytic activity.
RESULTS: Here, rare genomic characters are used to show that orthologs of neuroserpin, a prominent representative of vertebrate group 3 serpin genes, exist in early diverging deuterostomes and probably also in cnidarians, indicating that the origin of a mammalian serpin can be traced back far in the history of eumetazoans. A C-terminal address code assigning association with secretory pathway organelles is present in all neuroserpin orthologs, suggesting that supervision of cellular export/import routes by antiproteolytic serpins is an ancient trait, though subtle functional and compartmental specialisations have developed during their evolution. The results also suggest that massive changes in the exon-intron organisation of serpin genes have occurred along the lineage leading to vertebrate neuroserpin, in contrast with the immediately adjacent PDCD10 gene that is linked to its neighbour at least since divergence of echinoderms. The intron distribution pattern of closely adjacent and co-regulated genes thus may experience quite different fates during evolution of metazoans.
CONCLUSION: This study demonstrates that the analysis of microsynteny and other rare characters can provide insight into the intricate family history of metazoan serpins. Serpins with the capacity to defend the main cellular export/import routes against uncontrolled endogenous and/or foreign proteolytic activity represent an ancient trait in eukaryotes that has been maintained continuously in metazoans though subtle changes affecting function and subcellular location have evolved. It is shown that the intron distribution pattern of neuroserpin gene orthologs has undergone substantial rearrangements during metazoan evolution.
Figure 1. Gene structure-based phylogenetic classification of vertebrate serpins. Positions of introns refer to the human α1-antitrypsin sequence. A two amino acid indel present between positions 173 and 174 (α1-antitrypsin numbering) suggests that groups 1, 3, and 5 are more closely related to each other than to the other groups. Gene groups 2, 4, and 6 lack the 173/174 indel and depict an intron at position 192a, implying shared ancestry. Some group 1 members contain an additional intron at position 85c (not shown). For further details see references 20 and 21.
Figure 2. Genomic coordinates of the genes coding for neuroserpin homologs and flanking genes in metazoans. A vertical dashed line indicates neuroserpin (NEURO) orthologs. The genes coding for orthologs of neuroserpin and PDCD10 are consistently arranged in a head-to-head orientation at least since divergence of vertebrates and sea urchins. Orthologs are represented in identical colors. Serpin paralogs are represented as black arrows. The genes coding for neuroserpin and pancpin (PANC) share the characteristic intron distribution pattern of group 3 serpins maintained at least since the fish/tetrapod split.
Figure 3. Exon-intron organisation of the neuroserpin gene lineage. The Nematostella vectensis serpin gene Nve-Spn-1 is included, though orthology with the deuterostome counterparts is currently only supported by protein-based signature sequences. Specifications for intron positions and their phasing refer to mature human α1-antitrypsin. Only introns mapping to the serpin core domain (residues 33 to 394 of the reference) are considered.
Figure 4. C-terminal sequences of neuroserpin orthologs from deuterostomes and serpin Spn-1 from Nematostella vectensis. The numbering of amino acids refers to human α1-antitrypsin (top). Amino acids flanking the (putative) scissile bond are marked in turquoise, and the P1 position is indicated. Residues conserved in at least 70% of sequences are reproduced in white-on-black.
Figure 5. A discriminatory indel supports relationships of neuroserpin and homologs from sea urchins, lancelets, and Nematostella. Human representatives of vertebrate serpin groups 1, 3, and 5 containing the indel (marked in red), and from groups 2, 4 and 6 that lack the indel, are shown. The numbering of positions shown above the alignment refers to the sequence of mature human α1-antitrypsin. Positions conserved in at least 70% of sequences are represented in white-on-black printing.
Figure 6. Intron positions of PDCD10 genes in metazoans. Intron positions (white-on-black printing, phasing not indicated) were identified with GENEWISE and mapped onto the protein sequences. Intron positions conserved in at least two species are marked with an arrow head. Accession numbers for PDCD10 sequences: AAH16353 (human); XP_001186662 (Strongylocentrotus purpuratus); EDO34838 (Nematostella vectensis); AAF55190 (Drosophila melanogaster); CAA90115 (C. elegans).