A Comprehensive Phylogenetic Analysis of the Serpin Superfamily

Abstract

Serine protease inhibitors (serpins) are found in all kingdoms of life and play essential roles in multiple physiological processes. Owing to the diversity of the superfamily, phylogenetic analysis is challenging and prokaryotic serpins have been speculated to have been acquired from Metazoa through horizontal gene transfer (HGT) due to their unexpectedly high homology. Here we have leveraged a structural alignment of diverse serpins to generate a comprehensive 6000-sequence phylogeny that encompasses serpins from all kingdoms of life. We show that in addition to a central “hub” of highly conserved serpins, there has been extensive diversification of the superfamily into many novel functional clades. Our analysis indicates that the hub proteins are ancient and are similar because of convergent evolution, rather than the alternative hypothesis of HGT. This work clarifies longstanding questions in the evolution of serpins and provides new directions for research in the field of serpin biology.

Gut Serpinome: Emerging Evidence in IBD

“…Thus, an alternative hypothesis was proposed suggesting that serpins constitute an ancient superfamily that firstly appeared in prokaryotes prior to divergent evolution [ 120 ]. This hypothesis was supported by a recent phylogenetic analysis using 6000 non-redundant sequences that encompass serpins from all living kingdoms [ 124 ]. It was reported that most microbial serpins belong to two main groups (T and U), where a large proportion exhibits a predicted inhibitory function [ 124 ].…”

“…This hypothesis was supported by a recent phylogenetic analysis using 6000 non-redundant sequences that encompass serpins from all living kingdoms [ 124 ]. It was reported that most microbial serpins belong to two main groups (T and U), where a large proportion exhibits a predicted inhibitory function [ 124 ].…”

“…Interestingly, structural adaptation to high temperatures allows the thermopin to fold properly and preserve its inhibitory activity at high temperatures [ 115 ]. Of note, thermopin represents the only functionally characterized microbial serpin belonging to the group U [ 124 ]. Similar observations were reported with Thermoanaerobacter tengcongensis , an extremophile bacterium isolated from a hot spring (optimum growth temperature: 75 °C).…”

“…Similar observations were reported with Thermoanaerobacter tengcongensis , an extremophile bacterium isolated from a hot spring (optimum growth temperature: 75 °C). T. tengcongensis encodes an inhibitory serpin, tengpin, belonging to the group T, that inhibits NE and is able to form covalent complex [ 124 , 125 ]. Serpins were also characterized from the soil bacterium Clostridium thermocellum known to degrade cellulose.…”

“…The human gut microbiota encodes a large number of serpins, hereafter referred to as the gut serpinome, which mainly encompasses inhibitory functions [ 121 , 124 ]. However, only four serpins were functionally characterized till now.…”