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Exported on March 22, 2026 at 02:56 AM

Organism: Escherichia coli

Sequence:

MKNWKTLLLGIAMIANTSFAAPQVVDKVAAVVNNGVVLESDVDGLMQSVKLNAAQARQQLPDDATLRHQIMERLIMDQIILQMGQKMGVKISDEQLDQAIANIAKQNNMTLDQMRSRLAYDGLNYNTYRNQIRKEMIISEVRNNEVRRRITILPQEVESLAQQVGNQNDASTELNLSHILIPLPENPTSDQVNEAESQARAIVDQARNGADFGKLAIAHSADQQALNGGQMGWGRIQELPGIFAQALSTAKKGDIVGPIRSGVGFHILKVNDLRGESKNISVTEVHARHILLKPSPIMTDEQARVKLEQIAADIKSGKTTFAAAAKEFSQDPGSANQGGDLGWATPDIFDPAFRDALTRLNKGQMSAPVHSSFGWHLIELLDTRNVDKTDAAQKDRAYRMLMNRKFSEEAASWMQEQRASAYVKILSN

Thinking Trace

I begin with the InterPro architecture. The sequence is globally assigned to IPR050280 (Outer Membrane Protein Chaperone SurA family, residues 1–427) and IPR023034 (Peptidyl-prolyl isomerase SurA family, residues 9–428), indicating a SurA-class periplasmic chaperone that integrates folding and assembly functions. The N-terminal half is defined by IPR015391 (SurA N-terminal domain, residues 25–142) nested within IPR027304 (Trigger factor/SurA domain superfamily, residues 25–201). This N-terminal module is characteristic of periplasmic holdase/chaperone cores that cradle unfolded β-rich substrates and prevent premature aggregation. The C-terminal half transitions into IPR046357 (Peptidyl-prolyl cis-trans isomerase domain superfamily, residues 163–381) and the catalytic IPR000297 (PpiC-type peptidyl-prolyl cis-trans isomerase domain, residues 171–382), which is reinforced by IPR023058 (PpiC-type conserved site, residues 321–342). This ordered layout—an N-terminal SurA/trigger-factor-like chaperone platform followed by a C-terminal PpiC-type isomerase—creates a bipartite machine: the N-terminal domain binds and stabilizes unfolded outer-membrane and periplasmic enzymes, while the C-terminal PpiC module catalyzes cis-trans isomerization of proline bonds to accelerate productive folding.

This architecture directly causes peptidyl-prolyl cis-trans isomerase activity, matching GO:0003824 molecular function. The presence of the PpiC-type domain and its conserved site explains the catalytic chemistry that relieves kinetic bottlenecks during folding. Together, the SurA-family chaperone platform and the PpiC catalytic core define a folding catalyst that both binds substrates and actively reshapes them via proline isomerization.

From this molecular function, the biological role follows. By stabilizing unfolded β-barrel and periplasmic substrates and catalyzing proline isomerization, the protein drives protein folding and assembly pathways in the periplasm. These activities feed into envelope biogenesis—particularly the maturation and assembly of outer-membrane proteins and periplasmic enzymes—captured by the process of protein folding and assembly. Thus, the architecture supports the biological process of protein folding and assembly.

Cellular localization is specified by the SurA family assignment and the soluble periplasmic chaperone domains. The absence of transmembrane segments and the SurA lineage point to a soluble periplasmic residence consistent with a periplasm-localized folding hub. This aligns with a cellular component in the periplasm, where envelope-associated clients are matured.

Mechanistically, I hypothesize that the N-terminal SurA domain captures nascent or stress-unfolded periplasmic/outer-membrane proteins and prevents aggregation. The C-terminal PpiC module then catalyzes proline isomerization to accelerate attainment of native states. In this periplasmic assembly line, the chaperone likely cooperates with other envelope biogenesis factors—such as periplasmic folding factors and the β-barrel assembly pathway—to hand off properly folded substrates. Consequently, plausible interaction partners include periplasmic chaperones and assembly factors that coordinate substrate flow from the inner membrane to the outer membrane.

Functional Summary

A periplasmic folding catalyst that combines a SurA-like chaperone platform with a peptidyl-prolyl isomerase module to stabilize and mature unfolded envelope proteins. The N-terminal chaperone core binds β-rich periplasmic and outer-membrane substrates to prevent aggregation, while the C-terminal isomerase accelerates proline isomerization to drive productive folding and assembly within the periplasmic compartment of Escherichia coli.

UniProt Summary

May function as a chaperone and/or isomerase.

InterPro Domains

• Outer Membrane Protein Chaperone SurA (IPR050280, family) — residues 1-427
• Peptidyl-prolyl isomerase SurA (IPR023034, family) — residues 9-428
• Trigger factor/SurA domain superfamily (IPR027304, homologous_superfamily) — residues 25-201
• SurA N-terminal (IPR015391, domain) — residues 25-142
• Peptidyl-prolyl cis-trans isomerase domain superfamily (IPR046357, homologous_superfamily) — residues 163-381
• Peptidyl-prolyl cis-trans isomerase, PpiC-type (IPR000297, domain) — residues 171-382
• Peptidyl-prolyl cis-trans isomerase, PpiC-type, conserved site (IPR023058, conserved_site) — residues 321-342

GO Terms

Molecular Function: molecular_function (GO:0003674), binding (GO:0005488), peptidyl-prolyl cis-trans isomerase activity (GO:0003824), isomerase activity (GO:0016853), catalytic activity, acting on a protein (GO:0140096), protein binding (GO:0005515), cis-trans isomerase activity (GO:0016859), peptidyl-prolyl cis-trans isomerase activity (GO:0003755)

Biological Process: biological_process (GO:0008150), cellular process (GO:0009987), biological regulation (GO:0065007), homeostatic process (GO:0042592), regulation of biological quality (GO:0065008), cellular component organization or biogenesis (GO:0071840), cellular homeostasis (GO:0019725), protein folding (GO:0006457), cellular component organization (GO:0016043), cellular component biogenesis (GO:0044085), chaperone-mediated protein folding (GO:0061077), regulation of protein stability (GO:0031647), membrane biogenesis (GO:0044091), protein stabilization (GO:0050821), external encapsulating structure organization (GO:0045229), membrane organization (GO:0061024), cellular component assembly (GO:0022607), cell envelope organization (GO:0043163), membrane assembly (GO:0071709)

Cellular Component: cellular_component (GO:0005575), cellular anatomical entity (GO:0110165), periplasmic space (GO:0042597)

Generated by BioReason

BioReason Chat Export

Exported on March 22, 2026 at 02:56 AM

Organism: Escherichia coli

Sequence:

MKNWKTLLLGIAMIANTSFAAPQVVDKVAAVVNNGVVLESDVDGLMQSVKLNAAQARQQLPDDATLRHQIMERLIMDQIILQMGQKMGVKISDEQLDQAIANIAKQNNMTLDQMRSRLAYDGLNYNTYRNQIRKEMIISEVRNNEVRRRITILPQEVESLAQQVGNQNDASTELNLSHILIPLPENPTSDQVNEAESQARAIVDQARNGADFGKLAIAHSADQQALNGGQMGWGRIQELPGIFAQALSTAKKGDIVGPIRSGVGFHILKVNDLRGESKNISVTEVHARHILLKPSPIMTDEQARVKLEQIAADIKSGKTTFAAAAKEFSQDPGSANQGGDLGWATPDIFDPAFRDALTRLNKGQMSAPVHSSFGWHLIELLDTRNVDKTDAAQKDRAYRMLMNRKFSEEAASWMQEQRASAYVKILSN

Thinking Trace

I begin with the InterPro architecture. The sequence is globally assigned to IPR050280 (Outer Membrane Protein Chaperone SurA family, residues 1–427) and IPR023034 (Peptidyl-prolyl isomerase SurA family, residues 9–428), indicating a SurA-class periplasmic chaperone that integrates folding and assembly functions. The N-terminal half is defined by IPR015391 (SurA N-terminal domain, residues 25–142) nested within IPR027304 (Trigger factor/SurA domain superfamily, residues 25–201). This N-terminal module is characteristic of periplasmic holdase/chaperone cores that cradle unfolded β-rich substrates and prevent premature aggregation. The C-terminal half transitions into IPR046357 (Peptidyl-prolyl cis-trans isomerase domain superfamily, residues 163–381) and the catalytic IPR000297 (PpiC-type peptidyl-prolyl cis-trans isomerase domain, residues 171–382), which is reinforced by IPR023058 (PpiC-type conserved site, residues 321–342). This ordered layout—an N-terminal SurA/trigger-factor-like chaperone platform followed by a C-terminal PpiC-type isomerase—creates a bipartite machine: the N-terminal domain binds and stabilizes unfolded outer-membrane and periplasmic enzymes, while the C-terminal PpiC module catalyzes cis-trans isomerization of proline bonds to accelerate productive folding.

This architecture directly causes peptidyl-prolyl cis-trans isomerase activity, matching GO:0003824 molecular function. The presence of the PpiC-type domain and its conserved site explains the catalytic chemistry that relieves kinetic bottlenecks during folding. Together, the SurA-family chaperone platform and the PpiC catalytic core define a folding catalyst that both binds substrates and actively reshapes them via proline isomerization.

From this molecular function, the biological role follows. By stabilizing unfolded β-barrel and periplasmic substrates and catalyzing proline isomerization, the protein drives protein folding and assembly pathways in the periplasm. These activities feed into envelope biogenesis—particularly the maturation and assembly of outer-membrane proteins and periplasmic enzymes—captured by the process of protein folding and assembly. Thus, the architecture supports the biological process of protein folding and assembly.

Cellular localization is specified by the SurA family assignment and the soluble periplasmic chaperone domains. The absence of transmembrane segments and the SurA lineage point to a soluble periplasmic residence consistent with a periplasm-localized folding hub. This aligns with a cellular component in the periplasm, where envelope-associated clients are matured.

Mechanistically, I hypothesize that the N-terminal SurA domain captures nascent or stress-unfolded periplasmic/outer-membrane proteins and prevents aggregation. The C-terminal PpiC module then catalyzes proline isomerization to accelerate attainment of native states. In this periplasmic assembly line, the chaperone likely cooperates with other envelope biogenesis factors—such as periplasmic folding factors and the β-barrel assembly pathway—to hand off properly folded substrates. Consequently, plausible interaction partners include periplasmic chaperones and assembly factors that coordinate substrate flow from the inner membrane to the outer membrane.

Functional Summary

A periplasmic folding catalyst that combines a SurA-like chaperone platform with a peptidyl-prolyl isomerase module to stabilize and mature unfolded envelope proteins. The N-terminal chaperone core binds β-rich periplasmic and outer-membrane substrates to prevent aggregation, while the C-terminal isomerase accelerates proline isomerization to drive productive folding and assembly within the periplasmic compartment of Escherichia coli.

UniProt Summary

May function as a chaperone and/or isomerase.

InterPro Domains

• Outer Membrane Protein Chaperone SurA (IPR050280, family) — residues 1-427
• Peptidyl-prolyl isomerase SurA (IPR023034, family) — residues 9-428
• Trigger factor/SurA domain superfamily (IPR027304, homologous_superfamily) — residues 25-201
• SurA N-terminal (IPR015391, domain) — residues 25-142
• Peptidyl-prolyl cis-trans isomerase domain superfamily (IPR046357, homologous_superfamily) — residues 163-381
• Peptidyl-prolyl cis-trans isomerase, PpiC-type (IPR000297, domain) — residues 171-382
• Peptidyl-prolyl cis-trans isomerase, PpiC-type, conserved site (IPR023058, conserved_site) — residues 321-342

GO Terms

Molecular Function: molecular_function (GO:0003674), binding (GO:0005488), peptidyl-prolyl cis-trans isomerase activity (GO:0003824), isomerase activity (GO:0016853), catalytic activity, acting on a protein (GO:0140096), protein binding (GO:0005515), cis-trans isomerase activity (GO:0016859), peptidyl-prolyl cis-trans isomerase activity (GO:0003755)

Biological Process: biological_process (GO:0008150), cellular process (GO:0009987), biological regulation (GO:0065007), homeostatic process (GO:0042592), regulation of biological quality (GO:0065008), cellular component organization or biogenesis (GO:0071840), cellular homeostasis (GO:0019725), protein folding (GO:0006457), cellular component organization (GO:0016043), cellular component biogenesis (GO:0044085), chaperone-mediated protein folding (GO:0061077), regulation of protein stability (GO:0031647), membrane biogenesis (GO:0044091), protein stabilization (GO:0050821), external encapsulating structure organization (GO:0045229), membrane organization (GO:0061024), cellular component assembly (GO:0022607), cell envelope organization (GO:0043163), membrane assembly (GO:0071709)

Cellular Component: cellular_component (GO:0005575), cellular anatomical entity (GO:0110165), periplasmic space (GO:0042597)

Generated by BioReason

provider: falcon
model: Edison Scientific Literature
cached: false
start_time: '2026-03-22T17:57:47.962374'
end_time: '2026-03-22T18:09:08.275420'
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template_file: templates/gene_research_go_focused.md
template_variables:
organism: ECOLI
gene_id: surA
gene_symbol: surA
uniprot_accession: P0ABZ6
protein_description: 'RecName: Full=Chaperone SurA; AltName: Full=Peptidyl-prolyl
cis-trans isomerase SurA; Short=PPIase SurA; EC=5.2.1.8 {ECO:0000269|PubMed:8985185};
AltName: Full=Rotamase SurA; AltName: Full=Survival protein A; Flags: Precursor;'
gene_info: Name=surA; OrderedLocusNames=b0053, JW0052;
organism_full: Escherichia coli (strain K12).
protein_family: Not specified in UniProt
protein_domains: OMP_Chaperone_SurA. (IPR050280); PPIase_dom_sf. (IPR046357); PPIase_PpiC.
(IPR000297); PPIase_PpiC_CS. (IPR023058); PPIase_SurA. (IPR023034)
provider_config:
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citation_count: 29

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

• UniProt Accession: P0ABZ6
• Protein Description: RecName: Full=Chaperone SurA; AltName: Full=Peptidyl-prolyl cis-trans isomerase SurA; Short=PPIase SurA; EC=5.2.1.8 {ECO:0000269|PubMed:8985185}; AltName: Full=Rotamase SurA; AltName: Full=Survival protein A; Flags: Precursor;
• Gene Information: Name=surA; OrderedLocusNames=b0053, JW0052;
• Organism (full): Escherichia coli (strain K12).
• Protein Family: Not specified in UniProt
• Key Domains: OMP_Chaperone_SurA. (IPR050280); PPIase_dom_sf. (IPR046357); PPIase_PpiC. (IPR000297); PPIase_PpiC_CS. (IPR023058); PPIase_SurA. (IPR023034)

MANDATORY VERIFICATION STEPS:

1. Check if the gene symbol "surA" matches the protein description above
2. Verify the organism is correct: Escherichia coli (strain K12).
3. Check if protein family/domains align with what you find in literature
4. If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'surA' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene surA (gene ID: surA, UniProt: P0ABZ6) in ECOLI.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

• UniProt Accession: P0ABZ6
• Protein Description: RecName: Full=Chaperone SurA; AltName: Full=Peptidyl-prolyl cis-trans isomerase SurA; Short=PPIase SurA; EC=5.2.1.8 {ECO:0000269|PubMed:8985185}; AltName: Full=Rotamase SurA; AltName: Full=Survival protein A; Flags: Precursor;
• Gene Information: Name=surA; OrderedLocusNames=b0053, JW0052;
• Organism (full): Escherichia coli (strain K12).
• Protein Family: Not specified in UniProt
• Key Domains: OMP_Chaperone_SurA. (IPR050280); PPIase_dom_sf. (IPR046357); PPIase_PpiC. (IPR000297); PPIase_PpiC_CS. (IPR023058); PPIase_SurA. (IPR023034)

MANDATORY VERIFICATION STEPS:

1. Check if the gene symbol "surA" matches the protein description above
2. Verify the organism is correct: Escherichia coli (strain K12).
3. Check if protein family/domains align with what you find in literature
4. If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'surA' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene surA (gene ID: surA, UniProt: P0ABZ6) in ECOLI.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: SurA (UniProt P0ABZ6) in Escherichia coli K-12

1. Gene and Protein Identity

The surA gene in Escherichia coli strain K-12 encodes the periplasmic chaperone and peptidyl-prolyl cis-trans isomerase SurA (UniProt accession P0ABZ6) (monteiro2018proteomicidentificationof pages 73-75, fenn2024outermembraneprotein pages 1-2). SurA is a key component of the outer-membrane protein (OMP) biogenesis pathway (schiffrin2024dualclientbinding pages 1-2, fenn2024outermembraneprotein pages 1-2). SurA is synthesized with a cleavable N-terminal signal peptide (residues 1–20) that directs its export through the Sec translocon to the periplasm, where the mature protein (beginning at residue 21) carries out its chaperone function (fenn2024outermembraneprotein pages 1-2).

2. Structure and Domain Architecture

Recent structural studies reveal that SurA is a multi-domain ATP-independent chaperone comprising a central core domain and two parvulin-like peptidyl-prolyl isomerase (PPIase) domains designated P1 and P2 (schiffrin2024dualclientbinding pages 1-2, schiffrin2024dualclientbinding pages 8-9). Among these, only P2 is enzymatically active, while P1 and the core are primarily responsible for substrate recognition and binding (schiffrin2024dualclientbinding pages 1-2). Substrate binding is mediated by two conserved hotspots located in the core and P1 domains (schiffrin2024dualclientbinding pages 8-9). These hotspots preferentially engage aromatic-rich motifs characteristic of β-barrel OMPs (schiffrin2024dualclientbinding pages 1-2).

Bioinformatic analysis of 14,244 SurA homologs across bacteria revealed that only ~0.5% lack PPIase domains, underscoring their evolutionary conservation (schiffrin2024dualclientbinding pages 8-9). Importantly, while the parvulin (PPIase) domains can be removed without complete loss of in vivo chaperone activity, domain mobility is functionally critical: experimental cross-linking of P1 to the core domain causes OMP assembly defects in vivo, emphasizing that conformational flexibility is essential for SurA function (schiffrin2024dualclientbinding pages 8-9).

3. Function: Chaperone Activity and Peptidyl-Prolyl Isomerization

SurA protects newly translocated, unfolded OMPs from aggregation in the crowded, ATP-free periplasm and delivers them to the outer-membrane β-barrel assembly machinery (BAM complex) for folding and insertion (schiffrin2024dualclientbinding pages 1-2, fenn2024outermembraneprotein pages 1-2). The chaperone function is ATP-independent and does not rely on external energy input, but instead depends on structural plasticity and conformational dynamics (schiffrin2024dualclientbinding pages 1-2). SurA recognizes aromatic-rich motifs and the β-signal sequence found in integral OMPs and binds client proteins with weak, micromolar affinity (Kd ~1–14 µM), which is thought to permit efficient handoff to BAM (schiffrin2024dualclientbinding pages 1-2, fenn2024outermembraneprotein pages 9-11, schiffrin2024dualclientbinding pages 12-13).

In terms of substrate specificity, SurA preferentially handles unfolded β-barrel outer-membrane proteins (including substrates like OmpX, EspP, OmpA, OmpC, OmpF, and LptD), maintaining them in a folding-competent state prior to BAM-mediated insertion (fenn2024outermembraneprotein pages 9-11, fenn2024outermembraneprotein pages 7-9). SurA can engage clients in a manner that expands collapsed, non-native states (schiffrin2024dualclientbinding pages 1-2). It is important to note that SurA lacks the ability to recover already aggregated substrates, implying that it must engage nascent polypeptides early (troman2023interactionofthe pages 1-4).

4. Cellular Localization and Biogenesis Pathway

SurA operates exclusively in the periplasm of Gram-negative bacteria. Following synthesis in the cytoplasm, SurA is exported through the SecYEG translocon and its N-terminal signal peptide is cleaved by signal peptidase (fenn2024outermembraneprotein pages 1-2). Once in the periplasm, SurA participates in the OMP biogenesis pathway, which can be summarized as follows:

1. Early engagement at the Sec translocon. Recent biochemical and electron microscopy evidence demonstrates that SurA can bind to the inner-membrane holo-translocon (HTL), a complex comprising SecYEG, SecDF, and YidC, at the periplasmic side (troman2023interactionofthe pages 1-4, troman2023interactionofthe pages 4-8). This interaction is weak and transient but positions SurA to intercept nascent OMPs immediately upon their emergence from the Sec channel. AlphaFold2-guided models suggest contacts are mediated by periplasmic domains of SecDF and possibly YidC, with SurA's P1 and P2 PPIase domains implicated in this interface (troman2023interactionofthe pages 4-8).

2. Periplasmic trafficking. After initial capture, SurA maintains unfolded OMPs in solution and shields them from aggregation while traversing the periplasmic space toward the outer membrane (schiffrin2024dualclientbinding pages 1-2, troman2023interactionofthe pages 1-4).

3. Delivery to BAM. SurA interacts directly with the BAM complex through a β-augmentation mechanism, in which an N-terminal unstructured segment of SurA (specifically residues 23–28) forms a transient β-strand extension with the edge strand of the BamA POTRA-1 domain (around residues 75–80) (fenn2024outermembraneprotein pages 1-2, fenn2024outermembraneprotein pages 7-9). This interaction is critical for OMP handoff and BAM-mediated folding (fenn2024outermembraneprotein pages 1-2).

A recent landmark cryoEM study by Fenn et al. (2024) resolved multiple states of the BAM–SurA–OMP assembly cycle, termed Wait, Arrival, Handover, and Release (fenn2024outermembraneprotein pages 7-9, fenn2024outermembraneprotein media 1775a960, fenn2024outermembraneprotein media 46f060de). In the Wait state, SurA (in extended or compact conformations) binds BAM via POTRA-1. During Arrival, the OMP substrate is simultaneously bound to both SurA (between the core and P1 domains) and BamA. In the Handover state, the OMP engages the BamA lateral gate (β1 strand) for membrane insertion. Finally, in the Release state, SurA and the folded OMP dissociate from BAM, resetting the complex for another cycle (fenn2024outermembraneprotein media 1775a960, fenn2024outermembraneprotein media 46f060de).

5. Interaction Partners

5.1. β-Barrel Assembly Machinery (BAM) Complex

SurA's primary functional partner is the BAM complex, an outer-membrane insertase comprising the essential transmembrane protein BamA and accessory lipoproteins BamB, BamC, BamD, and BamE (fenn2024outermembraneprotein pages 9-11, fenn2024outermembraneprotein pages 1-2). The interaction with BAM is mediated primarily by BamA's POTRA-1 domain, with additional contacts to POTRA-2 and BamD observed in structural studies (fenn2024outermembraneprotein pages 9-11). Deletion of SurA residues 23–28 or introduction of proline substitutions at the β-augmentation interface (e.g., SurA(D26P) or BamA(R76P)) disrupts this interaction and causes severe outer-membrane assembly defects and increased permeability to antibiotics such as vancomycin (fenn2024outermembraneprotein pages 1-2). In contrast, conservative alanine mutations (D26A, R76A) do not affect the interface, indicating that backbone-mediated β-strand pairing (rather than side-chain contacts) is essential (fenn2024outermembraneprotein pages 1-2).

5.2. Sec Translocon and Holo-Translocon (HTL)

In addition to BAM, SurA associates with the inner-membrane Sec translocation machinery, including the core SecYEG translocon and its auxiliary components SecDF and YidC (troman2023interactionofthe pages 1-4, troman2023interactionofthe pages 4-8). This association is detected by biochemical cross-linking and electron microscopy and is thought to facilitate early capture of OMP clients immediately following their translocation across the inner membrane (troman2023interactionofthe pages 1-4, troman2023interactionofthe pages 4-8). The interaction is transient and weak, consistent with a handoff mechanism (troman2023interactionofthe pages 1-4).

5.3. Other Periplasmic Chaperones

SurA functions in concert with other periplasmic chaperones, notably Skp (a trimer that binds hydrophobic substrates and can refold aggregated OMPs) and DegP (a protease-chaperone that degrades terminally misfolded proteins or assists folding under stress) (troman2023interactionofthe pages 1-4, cottom2023targetingbamfor pages 1-3). SurA is considered the dominant or primary chaperone for OMP delivery to BAM, while Skp serves as an auxiliary or rescue pathway (troman2023interactionofthe pages 1-4, cottom2023targetingbamfor pages 1-3). In one functional assay, SurA required a threefold higher concentration than Skp to support BAM-mediated OmpT refolding in outer-membrane vesicles (OMVs), suggesting differential efficiency or stoichiometry (rath2023highthroughputscreeningof pages 1-2).

6. Phenotypes Associated with SurA Disruption

Deletion or functional impairment of SurA leads to marked defects in outer-membrane integrity and OMP homeostasis:

• Loss of major OMPs: Deletion of surA (ΔsurA) causes depletion of abundant OMPs including OmpC, OmpF, and LptD (fenn2024outermembraneprotein pages 9-11).
• Activation of envelope stress responses: Loss of SurA triggers the σE envelope stress response, reflecting accumulation of misfolded proteins in the periplasm (schiffrin2024dualclientbinding pages 1-2).
• Increased antibiotic permeability: ΔsurA strains are more permeable to large antibiotics such as vancomycin and rifampicin, indicating compromised outer-membrane barrier function (schiffrin2024dualclientbinding pages 1-2, fenn2024outermembraneprotein pages 1-2).
• Delayed signal sequence cleavage: Genetic evidence suggests that surA mutants delay cleavage of signal sequences (e.g., for LamB), consistent with a role near the Sec exit site (troman2023interactionofthe pages 1-4).
• Virulence defects: SurA is also implicated in the biogenesis of virulence-associated structures such as adhesins, pili, and autotransporters (schiffrin2024dualclientbinding pages 1-2).

Importantly, deletion of just six residues (Δ23–28) in the SurA N-terminus phenocopies full ΔsurA deletion in terms of outer-membrane defects, underscoring the critical importance of the BAM interaction interface (fenn2024outermembraneprotein pages 1-2, fenn2024outermembraneprotein pages 7-9). Despite these phenotypes, SurA is not strictly essential for E. coli growth under laboratory conditions, although its loss severely compromises fitness (fenn2024outermembraneprotein pages 9-11).

7. Quantitative Data from Recent Studies

8. Real-World Applications and Antimicrobial Relevance

The SurA–BAM axis is emerging as an attractive target for antibiotic discovery against multidrug-resistant Gram-negative pathogens (rath2023highthroughputscreeningof pages 1-2, fenn2024outermembraneprotein pages 9-11, cottom2023targetingbamfor pages 1-3). Because the BAM complex is essential and highly conserved across Gram-negative bacteria, and because the outer membrane is a critical barrier for pathogen survival, disrupting OMP biogenesis offers a novel mode of action distinct from traditional antibiotics (cottom2023targetingbamfor pages 1-3).

8.1. High-Throughput Inhibitor Screening

A recent study by Rath et al. (2023) developed an outer-membrane vesicle (OMV)–based functional assay for BAM that preserves the native lipopolysaccharide (LPS) and membrane environment (rath2023highthroughputscreeningof pages 1-2). This assay uses SurA to deliver unfolded OmpT to BAM, and activity is monitored via cleavage of a self-quenched fluorescent peptide. The assay was miniaturized to 1536-well format and validated with a Z' factor of 0.7, enabling high-throughput screening of large compound libraries (rath2023highthroughputscreeningof pages 1-2, rath2023highthroughputscreeningof pages 6-7). Darobactin, a natural product BAM inhibitor, showed an IC50 of ~230 nM in OMVs, tenfold more potent than in synthetic reconstitutions, highlighting the importance of native membranes for physiological relevance (rath2023highthroughputscreeningof pages 1-2, rath2023highthroughputscreeningof pages 6-7). Pilot screens of ~10,000 compounds identified 39 hits with ≥50% inhibition, with the best hits exhibiting IC50 values around 40 µM (rath2023highthroughputscreeningof pages 6-7).

8.2. Targeting the SurA–BamA Interface

Structural insights from Fenn et al. (2024) propose that the SurA–BamA POTRA-1 interaction (the β-augmentation between SurA residues 23–28 and BamA residues ~75–80) could itself be a druggable interface to block OMP delivery (fenn2024outermembraneprotein pages 9-11, fenn2024outermembraneprotein pages 1-2). Disruption of this interface (via mutations or small-molecule inhibitors) phenocopies loss of SurA and compromises envelope integrity (fenn2024outermembraneprotein pages 1-2).

8.3. Synergy with BAM-Targeting Compounds

Genetic studies show that deletion of surA sensitizes E. coli to the BAM-targeting small molecule MRL-494, supporting a functional link between SurA and BAM and validating the pathway as a therapeutic target (cottom2023targetingbamfor pages 7-8). Other BAM inhibitors, including darobactins and dynobactins, are under investigation, with the SurA–BAM complex serving as a platform for mechanistic and drug-discovery studies (fenn2024outermembraneprotein pages 15-16, fenn2024outermembraneprotein pages 9-11).

9. Recent Developments (2023–2024)

The years 2023–2024 witnessed major advances in understanding SurA structure, mechanism, and potential as a therapeutic target:

• Fenn et al. (2024, Nature Communications) resolved cryoEM structures of multiple BAM–SurA–OMP assembly states (Wait, Arrival, Handover, Release), revealing the dynamic choreography of OMP delivery and the critical role of SurA's N-terminal β-augmentation with BamA POTRA-1 (September 2024; https://doi.org/10.1038/s41467-024-51358-x) (fenn2024outermembraneprotein pages 1-2, fenn2024outermembraneprotein pages 7-9, fenn2024outermembraneprotein media 1775a960, fenn2024outermembraneprotein media 46f060de).

• Schiffrin et al. (2024, Nature Communications) used NMR, single-molecule FRET, and crosslinking to define dual client-binding sites in SurA (core and P1 domains), demonstrate autoinhibition of the core by P1, and characterize substrate-induced conformational changes (September 2024; https://doi.org/10.1038/s41467-024-52021-1) (schiffrin2024dualclientbinding pages 1-2, schiffrin2024dualclientbinding pages 8-9, schiffrin2024dualclientbinding pages 12-13).

• Troman et al. (2023, Biochemical Journal) provided the first biochemical and EM evidence for SurA binding to the inner-membrane Sec holo-translocon (SecYEG-SecDF-YidC), suggesting recruitment at the protein export exit site and a mechanism for immediate chaperone engagement of nascent OMPs (September 2023; https://doi.org/10.1101/2022.09.14.507990) (troman2023interactionofthe pages 1-4, troman2023interactionofthe pages 4-8).

• Rath et al. (2023, Nature Communications) described a robust OMV-based, high-throughput functional assay for BAM that incorporates SurA, validated it with darobactin (IC50 ~230 nM), and demonstrated miniaturization to 1536-well format suitable for screening million-compound libraries (September 2023; https://doi.org/10.1038/s41467-023-41445-w) (rath2023highthroughputscreeningof pages 1-2, rath2023highthroughputscreeningof pages 6-7).

• Cottom et al. (2023, Antibiotics) and Xu et al. (2023, Molecules) reviewed the therapeutic potential of targeting BAM, highlighting SurA as part of the OMP biogenesis pathway and noting that surA deletion sensitizes cells to BAM inhibitors like MRL-494 (March and April 2023; https://doi.org/10.3390/antibiotics12040679; https://doi.org/10.3390/molecules28093758) (cottom2023targetingbamfor pages 7-8, cottom2023targetingbamfor pages 1-3).

Table: This table summarizes the current functional annotation of E. coli K-12 SurA (UniProt P0ABZ6), emphasizing 2023-2024 primary studies and quantitative findings. It is useful as a compact evidence map for localization, mechanism, pathway placement, phenotypes, and antimicrobial relevance.

10. Summary

SurA (UniProt P0ABZ6) is a periplasmic, ATP-independent chaperone and peptidyl-prolyl isomerase essential for maintaining outer-membrane integrity in Escherichia coli K-12. It consists of a core domain and two PPIase domains (P1, P2), with only P2 enzymatically active. SurA captures unfolded β-barrel OMPs via aromatic-rich motifs, prevents their aggregation, and delivers them to the BAM complex through a dynamic, backbone-mediated β-augmentation interaction with BamA POTRA-1. Loss of SurA causes outer-membrane defects, σE stress, and increased antibiotic permeability. Recent cryoEM structures and biochemical studies (2023–2024) have elucidated the sequential states of BAM–SurA-mediated OMP assembly and the dual client-binding sites in SurA. The SurA–BAM axis is now recognized as a promising antibacterial target, with native-membrane functional assays enabling high-throughput screening of BAM inhibitors. Together, these findings position SurA at the intersection of fundamental bacterial physiology and next-generation antimicrobial discovery.

Key citations:
- Fenn et al., 2024, Nat Commun (fenn2024outermembraneprotein pages 1-2, fenn2024outermembraneprotein pages 9-11, fenn2024outermembraneprotein pages 7-9, fenn2024outermembraneprotein media 1775a960, fenn2024outermembraneprotein media 46f060de)
- Schiffrin et al., 2024, Nat Commun (schiffrin2024dualclientbinding pages 1-2, schiffrin2024dualclientbinding pages 8-9, schiffrin2024dualclientbinding pages 12-13)
- Troman et al., 2023, Biochem J (troman2023interactionofthe pages 1-4, troman2023interactionofthe pages 4-8)
- Rath et al., 2023, Nat Commun (rath2023highthroughputscreeningof pages 1-2, rath2023highthroughputscreeningof pages 6-7)
- Cottom et al., 2023, Antibiotics (cottom2023targetingbamfor pages 7-8, cottom2023targetingbamfor pages 1-3)

References

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6. (schiffrin2024dualclientbinding pages 12-13): Bob Schiffrin, Joel A. Crossley, Martin Walko, Jonathan M. Machin, G. Nasir Khan, Iain W. Manfield, Andrew J. Wilson, David J. Brockwell, Tomas Fessl, Antonio N. Calabrese, Sheena E. Radford, and Anastasia Zhuravleva. Dual client binding sites in the atp-independent chaperone sura. Nature Communications, Sep 2024. URL: https://doi.org/10.1038/s41467-024-52021-1, doi:10.1038/s41467-024-52021-1. This article has 5 citations and is from a highest quality peer-reviewed journal.

7. (fenn2024outermembraneprotein pages 7-9): Katherine L. Fenn, Jim E. Horne, Joel A. Crossley, Nils Böhringer, Romany J. Horne, Till F. Schäberle, Antonio N. Calabrese, Sheena E. Radford, and Neil A. Ranson. Outer membrane protein assembly mediated by bam-sura complexes. Nature Communications, Sep 2024. URL: https://doi.org/10.1038/s41467-024-51358-x, doi:10.1038/s41467-024-51358-x. This article has 30 citations and is from a highest quality peer-reviewed journal.

8. (troman2023interactionofthe pages 1-4): Lucy Troman, Sara Alvira, Bertram Daum, Vicki A. M. Gold, and Ian Collinson. Interaction of the periplasmic chaperone sura with the inner membrane protein secretion (sec) machinery. Biochemical Journal, 480:283-296, Sep 2023. URL: https://doi.org/10.1101/2022.09.14.507990, doi:10.1101/2022.09.14.507990. This article has 17 citations and is from a domain leading peer-reviewed journal.

9. (troman2023interactionofthe pages 4-8): Lucy Troman, Sara Alvira, Bertram Daum, Vicki A. M. Gold, and Ian Collinson. Interaction of the periplasmic chaperone sura with the inner membrane protein secretion (sec) machinery. Biochemical Journal, 480:283-296, Sep 2023. URL: https://doi.org/10.1101/2022.09.14.507990, doi:10.1101/2022.09.14.507990. This article has 17 citations and is from a domain leading peer-reviewed journal.

10. (fenn2024outermembraneprotein media 1775a960): Katherine L. Fenn, Jim E. Horne, Joel A. Crossley, Nils Böhringer, Romany J. Horne, Till F. Schäberle, Antonio N. Calabrese, Sheena E. Radford, and Neil A. Ranson. Outer membrane protein assembly mediated by bam-sura complexes. Nature Communications, Sep 2024. URL: https://doi.org/10.1038/s41467-024-51358-x, doi:10.1038/s41467-024-51358-x. This article has 30 citations and is from a highest quality peer-reviewed journal.

11. (fenn2024outermembraneprotein media 46f060de): Katherine L. Fenn, Jim E. Horne, Joel A. Crossley, Nils Böhringer, Romany J. Horne, Till F. Schäberle, Antonio N. Calabrese, Sheena E. Radford, and Neil A. Ranson. Outer membrane protein assembly mediated by bam-sura complexes. Nature Communications, Sep 2024. URL: https://doi.org/10.1038/s41467-024-51358-x, doi:10.1038/s41467-024-51358-x. This article has 30 citations and is from a highest quality peer-reviewed journal.

12. (cottom2023targetingbamfor pages 1-3): Claire Overly Cottom, Robert Stephenson, Lindsey Wilson, and Nicholas Noinaj. Targeting bam for novel therapeutics against pathogenic gram-negative bacteria. Antibiotics, 12:679, Mar 2023. URL: https://doi.org/10.3390/antibiotics12040679, doi:10.3390/antibiotics12040679. This article has 24 citations.

13. (rath2023highthroughputscreeningof pages 1-2): Parthasarathi Rath, Adrian Hermann, Ramona Schaefer, Elia Agustoni, Jean-Marie Vonach, Martin Siegrist, Christian Miscenic, Andreas Tschumi, Doris Roth, Christoph Bieniossek, and Sebastian Hiller. High-throughput screening of bam inhibitors in native membrane environment. Nature Communications, Sep 2023. URL: https://doi.org/10.1038/s41467-023-41445-w, doi:10.1038/s41467-023-41445-w. This article has 12 citations and is from a highest quality peer-reviewed journal.

14. (rath2023highthroughputscreeningof pages 6-7): Parthasarathi Rath, Adrian Hermann, Ramona Schaefer, Elia Agustoni, Jean-Marie Vonach, Martin Siegrist, Christian Miscenic, Andreas Tschumi, Doris Roth, Christoph Bieniossek, and Sebastian Hiller. High-throughput screening of bam inhibitors in native membrane environment. Nature Communications, Sep 2023. URL: https://doi.org/10.1038/s41467-023-41445-w, doi:10.1038/s41467-023-41445-w. This article has 12 citations and is from a highest quality peer-reviewed journal.

15. (cottom2023targetingbamfor pages 7-8): Claire Overly Cottom, Robert Stephenson, Lindsey Wilson, and Nicholas Noinaj. Targeting bam for novel therapeutics against pathogenic gram-negative bacteria. Antibiotics, 12:679, Mar 2023. URL: https://doi.org/10.3390/antibiotics12040679, doi:10.3390/antibiotics12040679. This article has 24 citations.

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Citations

1. fenn2024outermembraneprotein pages 1-2
2. schiffrin2024dualclientbinding pages 1-2
3. schiffrin2024dualclientbinding pages 8-9
4. troman2023interactionofthe pages 1-4
5. troman2023interactionofthe pages 4-8
6. fenn2024outermembraneprotein pages 9-11
7. rath2023highthroughputscreeningof pages 1-2
8. rath2023highthroughputscreeningof pages 6-7
9. cottom2023targetingbamfor pages 1-3
10. cottom2023targetingbamfor pages 7-8
11. monteiro2018proteomicidentificationof pages 73-75
12. schiffrin2024dualclientbinding pages 12-13
13. fenn2024outermembraneprotein pages 7-9
14. fenn2024outermembraneprotein pages 15-16
15. https://doi.org/10.1038/s41467-024-51358-x
16. https://doi.org/10.1038/s41467-024-52021-1
17. https://doi.org/10.1101/2022.09.14.507990
18. https://doi.org/10.1038/s41467-023-41445-w
19. https://doi.org/10.3390/antibiotics12040679;
20. https://doi.org/10.3390/molecules28093758
21. https://doi.org/10.1038/s41467-024-51358-x;
22. https://doi.org/10.1101/2022.09.14.507990;
23. https://doi.org/10.1038/s41467-024-52021-1;
24. https://doi.org/10.1038/s41467-023-41445-w;
25. https://doi.org/10.1038/s41467-024-51358-x,
26. https://doi.org/10.1038/s41467-024-52021-1,
27. https://doi.org/10.1101/2022.09.14.507990,
28. https://doi.org/10.3390/antibiotics12040679,
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BioReason-Pro RL Review: surA (E. coli)

Source: surA-deep-research-bioreason-rl.md

• Correctness: 4/5
• Completeness: 4/5

Functional Summary Review

The BioReason functional summary describes surA as:

A periplasmic folding catalyst that combines a SurA-like chaperone platform with a peptidyl-prolyl isomerase module to stabilize and mature unfolded envelope proteins. The N-terminal chaperone core binds beta-rich periplasmic and outer-membrane substrates to prevent aggregation, while the C-terminal isomerase accelerates proline isomerization to drive productive folding and assembly within the periplasmic compartment of Escherichia coli.

This is a strong summary that accurately captures most of SurA's key features:
- Periplasmic localization (correctly identified, unlike CpxP, Skp, and Spy)
- Dual function: chaperone + PPIase
- N-terminal chaperone domain binds beta-barrel substrates
- Recognition of unfolded outer membrane proteins
- Prevention of aggregation

The summary correctly identifies the bipartite architecture (N-terminal chaperone + C-terminal PPIase). The thinking trace accurately describes the InterPro domains including IPR050280 (SurA family), IPR015391 (SurA N-terminal), and IPR000297 (PpiC-type PPIase).

Minor gaps:
- Does not emphasize that the PPIase activity is dispensable for in vivo chaperone function -- a key finding from the curated review
- Does not mention that SurA is the PRIMARY pathway for OMP biogenesis (with Skp/DegP as backup)
- Does not mention delivery to the BAM complex specifically
- Does not mention the sigmaE stress response activation upon SurA loss
- The summary overstates the PPIase contribution to function by placing it as a co-equal partner with the chaperone domain; in reality the chaperone function is dominant

The thinking trace's claim that "catalytic activity" (GO:0003824) is the primary molecular function is somewhat misleading; the curated review places protein folding chaperone (GO:0044183) as the primary function.

Comparison with interpro2go:

The curated review's interpro2go annotations include periplasmic space (GO:0030288, correct), peptide binding (GO:0042277, correct), outer membrane assembly (GO:0043165, correct), and protein stabilization (GO:0050821, correct). BioReason recapitulates these interpro2go annotations well in its narrative. The model adds value by correctly synthesizing the domain architecture into a bipartite chaperone-PPIase model. However, the narrative overweights the PPIase function relative to the chaperone function, which is a subtle but important nuance that interpro2go alone would not capture.

Notes on thinking trace

The trace correctly identifies the trigger factor/SurA domain superfamily (IPR027304) connection, which is structurally informative. The reasoning from domain architecture to function is sound. The mention of "periplasmic chaperones and assembly factors" as interaction partners is appropriate.