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The Two Distinct Types of SecA2-Dependent Export Systems

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  • Authors: Miriam Braunstein1, Barbara A. Bensing2, Paul M. Sullam3
  • Editors: Maria Sandkvist4, Eric Cascales5, Peter J. Christie6
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599; 2: Department of Medicine, San Francisco Veterans Affairs Medical Center and the University of California, San Francisco, CA 94121; 3: Department of Medicine, San Francisco Veterans Affairs Medical Center and the University of California, San Francisco, CA 94121; 4: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan; 5: CNRS Aix-Marseille Université, Mediterranean Institute of Microbiology, Marseille, France; 6: Department of Microbiology and Molecular Genetics, McGovern Medical School, Houston, Texas
  • Source: microbiolspec June 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.PSIB-0025-2018
  • Received 19 December 2018 Accepted 07 May 2019 Published 19 June 2019
  • Miriam Braunstein, [email protected]; Paul M. Sullam, [email protected]
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  • Abstract:

    In addition to SecA of the general Sec system, many Gram-positive bacteria, including mycobacteria, express SecA2, a second, transport-associated ATPase. SecA2s can be subdivided into two mechanistically distinct types: (i) SecA2s that are part of the accessory Sec (aSec) system, a specialized transporter mediating the export of a family of serine-rich repeat (SRR) glycoproteins that function as adhesins, and (ii) SecA2s that are part of multisubstrate systems, in which SecA2 interacts with components of the general Sec system, specifically the SecYEG channel, to export multiple types of substrates. Found mainly in streptococci and staphylococci, the aSec system also contains SecY2 and novel accessory Sec proteins (Asps) that are required for optimal export. Asp2 also acetylates glucosamine residues on the SRR domains of the substrate during transport. Targeting of the SRR substrate to SecA2 and the aSec translocon is mediated by a specialized signal peptide. Multisubstrate SecA2 systems are present in mycobacteria, corynebacteria, listeriae, clostridia, and some bacillus species. Although most substrates for this SecA2 have canonical signal peptides that are required for export, targeting to SecA2 appears to depend on structural features of the mature protein. The feature of the mature domains of these proteins that renders them dependent on SecA2 for export may be their potential to fold in the cytoplasm. The discovery of aSec and multisubstrate SecA2 systems expands our appreciation of the diversity of bacterial export pathways. Here we present our current understanding of the mechanisms of each of these SecA2 systems.

  • Citation: Braunstein M, Bensing B, Sullam P. 2019. The Two Distinct Types of SecA2-Dependent Export Systems. Microbiol Spectrum 7(3):PSIB-0025-2018. doi:10.1128/microbiolspec.PSIB-0025-2018.

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/content/journal/microbiolspec/10.1128/microbiolspec.PSIB-0025-2018
2019-06-19
2020-10-28

Abstract:

In addition to SecA of the general Sec system, many Gram-positive bacteria, including mycobacteria, express SecA2, a second, transport-associated ATPase. SecA2s can be subdivided into two mechanistically distinct types: (i) SecA2s that are part of the accessory Sec (aSec) system, a specialized transporter mediating the export of a family of serine-rich repeat (SRR) glycoproteins that function as adhesins, and (ii) SecA2s that are part of multisubstrate systems, in which SecA2 interacts with components of the general Sec system, specifically the SecYEG channel, to export multiple types of substrates. Found mainly in streptococci and staphylococci, the aSec system also contains SecY2 and novel accessory Sec proteins (Asps) that are required for optimal export. Asp2 also acetylates glucosamine residues on the SRR domains of the substrate during transport. Targeting of the SRR substrate to SecA2 and the aSec translocon is mediated by a specialized signal peptide. Multisubstrate SecA2 systems are present in mycobacteria, corynebacteria, listeriae, clostridia, and some bacillus species. Although most substrates for this SecA2 have canonical signal peptides that are required for export, targeting to SecA2 appears to depend on structural features of the mature protein. The feature of the mature domains of these proteins that renders them dependent on SecA2 for export may be their potential to fold in the cytoplasm. The discovery of aSec and multisubstrate SecA2 systems expands our appreciation of the diversity of bacterial export pathways. Here we present our current understanding of the mechanisms of each of these SecA2 systems.

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Figures

Image of FIGURE 1
FIGURE 1

Models for the general Sec system, the aSec system, and the multisubstrate SecA2 system. General Sec system. SecA uses ATP hydrolysis to export cytoplasmic preproteins through the SecYEG channel in an unfolded state. SecDFYajC are auxiliary components that enhance export efficiency. Sec signal peptides (black rectangle) target preproteins (blue ribbon) for export through SecYEG. Following export across the membrane, the signal peptide is cleaved by a signal peptidase (SP) and the resulting mature protein folds into its proper conformation. aSec system. The model depicted is largely based on studies of the SecA2 system. Glycosylation of the preprotein (pink ribbon) with GlcNAc (blue squares) and Glc (blue circles) likely occurs cotranslationally. The positively charged N region of the signal peptide (black rectangle) targets the preprotein to anionic phospholipids, which aids the localization with SecA2. Transport through the SecY2/Asp4/5 channel requires a specific sequence in the mature region of the preprotein, as well as Asp1 to Asp3. Asp2 is a bifunctional protein that also mediates O-acetylation of GlcNAc moieties (red square). Cleavage of the signal peptide is thought to be carried out by the general SP. Multisubstrate SecA2 system. The model depicted is largely based on studies of the mycobacterial SecA2 system. SecA2 works with the canonical SecYEG channel and possibly SecA1 to export its specific subset of preproteins (green ribbon). The majority of SecA2 substrates are synthesized as preproteins with a signal peptide (black rectangle) that is cleaved in association with export. The mature domain, not the signal peptide, of a preprotein determines if a protein is exported by this SecA2 system. It is proposed that the mature domain of a SecA2 substrate has the propensity to fold in the cytoplasm and that the role of SecA2 is to facilitate the export of such proteins, in an unfolded state, through the SecYEG channel. Additional factors are likely to work with SecA2 in the pathway (purple symbol). The role of SecA2 in exporting moonlighting proteins that lack signal peptides is unclear and not depicted in the model.

Source: microbiolspec June 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.PSIB-0025-2018
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Image of FIGURE 2
FIGURE 2

Genomic regions encoding aSec and multisubstrate SecA2 proteins. aSec loci. Shown are representative aSec loci in Gram-positive bacteria. The gene is shown in black and the other genes encoding core components of the aSec translocase (SecY2 and Asps) are colored yellow. Genes encoding glycosyltransferases (Gtf) and proteins involved in carbohydrate modifications are shown in orange. Genes encoding exported SecA2 substrates are shown in blue. In , the Asp orthologues are called Gap1 to Gap3. In , the genes are located distal to the locus but are required for the first step of O-GlcNAcylation of the substrate ( 89 ) and thus may be functionally analogous to the pairs found in other aSec loci. Multisubstrate SecA2 loci. Shown are representative multisubstrate genes and neighboring genomic regions in Gram-positive bacteria. The gene is shown in black, and genes encoding SecA2 substrates are shown in blue. Candidate genes for additional SecA2 substrates are shown with blue stripes. Substrates encoded elsewhere in the genome are not shown. Additional proteins with roles in SecA2-dependent export are encoded by genes shown in pink. Genes encoding proteins with no known connection to export are shown in gray.

Source: microbiolspec June 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.PSIB-0025-2018
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Image of FIGURE 3
FIGURE 3

GspB domains and features of the N-terminal signal peptide (SP). (Top) Domains of the SRR glycoprotein GspB. AST, aSec transport domain; SRR1 and SRR2, serine-rich repeat regions 1 and 2, respectively; BR, ligand binding region; CWA, cell wall-anchoring domain. The CWA includes a transmembrane segment, an LPxTG motif, and a charged C-terminal tail ( 90 ). (Bottom) The GspB signal peptide has the tripartite structure of canonical signal peptides: the N-terminal (N), hydrophobic core (H), and cleavage (C) regions. However, the N region is substantially longer than typical signal peptides and includes a KxYKxGKxW motif (red). Glycine residues in the H region are also indicated in red.

Source: microbiolspec June 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.PSIB-0025-2018
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Image of FIGURE 4
FIGURE 4

Domain organization in the canonical SecA of and SecA2 proteins of and . Domains were identified in SecA2 proteins by alignment with SecA using published domain boundaries ( 91 ). NBD, nucleotide binding domain; PPXD, preprotein cross-linking domain; HSD, helical scaffold domain; HWD, helical wing domain; IRA, intramolecular regulator of ATPase activity; CTD, C-terminal domain. Compared to the canonical SecA, SecA2 proteins have deletions in the HWD and CTD regions. Amino acid number in the protein sequence is shown below each schematic.

Source: microbiolspec June 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.PSIB-0025-2018
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