Abstract
The rhomboid family of serine proteases occurs in all domains of life. Its members contain at least six hydrophobic membrane-spanning helices, with an active site serine located deep within the hydrophobic interior of the plasma membrane. The model member GlpG from Escherichia coli is heavily studied through engineered mutant forms, varied model substrates, and multiple X-ray crystal studies, yet its relationship to endogenous substrates is not well understood. Here we describe an apparent membrane anchoring C-terminal homology domain that appears in numerous genera including Shewanella, Vibrio, Acinetobacter, and Ralstonia, but excluding Escherichia and Haemophilus. Individual genomes encode up to thirteen members, usually homologous to each other only in this C-terminal region. The domain's tripartite architecture consists of motif, transmembrane helix, and cluster of basic residues at the protein C-terminus, as also seen with the LPXTG recognition sequence for sortase A and the PEP-CTERM recognition sequence for exosortase. Partial Phylogenetic Profiling identifies a distinctive rhomboid-like protease subfamily almost perfectly co-distributed with this recognition sequence. This protease subfamily and its putative target domain are hereby renamed rhombosortase and GlyGly-CTERM, respectively. The protease and target are encoded by consecutive genes in most genomes with just a single target, but far apart otherwise. The signature motif of the Rhombo-CTERM domain, often SGGS, only partially resembles known cleavage sites of rhomboid protease family model substrates. Some protein families that have several members with C-terminal GlyGly-CTERM domains also have additional members with LPXTG or PEP-CTERM domains instead, suggesting there may be common themes to the post-translational processing of these proteins by three different membrane protein superfamilies.
Highlights
LPXTG and PEP-CTERM provide examples of C-terminal protein sorting signalsMany members of the Firmicutes have collections of proteins that share similar C-terminal regions with a tripartite architecture consisting of the signature motif LPXTG, a transmembrane (TM) alpha helix, and a cluster of basic residues [1]
A search in Shewanella genomes for previously unrecognized C-terminal homology domains with the LPXTG/PEPCTERM-like architecture found an apparent sorting signal with a glycine-rich signature motif
The difference in post-translational processing for the same protein in these two different species suggests that specificities may differ for different rhomboid family intramembrane proteases found in bacteria
Summary
LPXTG and PEP-CTERM provide examples of C-terminal protein sorting signalsMany members of the Firmicutes have collections of proteins that share similar C-terminal regions with a tripartite architecture consisting of the signature motif LPXTG, a transmembrane (TM) alpha helix, and a cluster of basic residues [1]. LPXTG and PEP-CTERM provide examples of C-terminal protein sorting signals. The PEP-CTERM homology domain, found only in Gramnegative bacteria, has the same C-terminal location in proteins and same tripartite architecture as LPXTG, but has a different signature motif, Pro-Glu-Pro [4]. As with LPXTG, proteins bearing PEP-CTERM domains are found in a minority of species, but species with at least one often have twenty or more. Exosortase, the proposed sorting enzyme for PEP-CTERM domain proteins, is a highly hydrophobic protein with eight predicted transmembrane helices. Just as all species with LPXTG proteins have a sortase, all species with PEP-CTERM proteins have an exosortase. This relationship led to the in silico discovery of exosortase by Partial Phylogenetic Profiling [4]. A similar C-terminal putative sorting signal, PGF-CTERM, pairs with archaeosortase A, a distant homolog of exosortase, and appears involved in the processing of S-layer glycoproteins [5]
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