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Structural inferences for Cholera toxin mutations in Vibrio cholerae.

Shamini G, Ravichandran M, Sinnott JT, Somboonwit C, Sidhu HS, Shapshak P, Kangueane P - Bioinformation (2011)

Bottom Line: The formation of the AB(5) complex involves inter-subunit residue-residue interactions at the protein-protein interfaces.Hence, these mutations, at the structurally relevant positions, are of importance for the understanding of pathogenesis by several serogroups.This is also of significance in the improvement of recombinant CT protein complex analogs for vaccine design and their use against multiple serogroups.

View Article: PubMed Central - PubMed

ABSTRACT
Cholera is a global disease that has persisted for millennia. The cholera toxin (CT) from Vibrio cholerae is responsible for the clinical symptoms of cholera. This toxin is a hetero-hexamer (AB(5)) complex consisting of a subunit A (CTA) with a pentamer (B(5)) of subunit B (CTB). The importance of the AB(5) complex for pathogenesis is established for the wild type O1 serogroup using known structural and functional data. However, its role is not yet documented in other known serogroups harboring sequence level residue mutations. The sequences for the toxin from different serogroups are available in GenBank (release 177). Sequence analysis reveals mutations at several sequence positions in the toxin across serogroups. Therefore, it is of interest to locate the position of these mutations in the AB(5) structure to infer complex assembly for its functional role in different serogroups. We show that mutations in the CTA are at the solvent exposed regions of the AB(5) complex, whereas those in the CTB are at the CTB/CTB interface of the homo-pentamer complex. Thus, the role of mutations at the CTB/CTB interface for B(5) complex assembly is implied. It is observed that these mutations are often non-synonymous (e.g. polar to non-polar or vice versa). The formation of the AB(5) complex involves inter-subunit residue-residue interactions at the protein-protein interfaces. Hence, these mutations, at the structurally relevant positions, are of importance for the understanding of pathogenesis by several serogroups. This is also of significance in the improvement of recombinant CT protein complex analogs for vaccine design and their use against multiple serogroups.

No MeSH data available.


Related in: MedlinePlus

Structural model of a cholera toxin (CT). CT is a hetero-hexamericcomplex (AB5) consisting of CTA (194 residues A1 and 46 residues A2) andCTB (103 residues) pentamer with D, E, F, G and H chains.
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Figure 1: Structural model of a cholera toxin (CT). CT is a hetero-hexamericcomplex (AB5) consisting of CTA (194 residues A1 and 46 residues A2) andCTB (103 residues) pentamer with D, E, F, G and H chains.

Mentions: CT, also known as choleragen, is a hetero-hexameric AB5 complex in structure(Figure 1) [29–31] and is composed of an enzymatic A subunit (CTA) and acell targeting B subunit (CTB) [32–34]. The enzymatically activated A subunitcatalyzes adenylate cyclase to cause massive excretion of electrolytes frombowel [35,36]. However, the homo-pentamer B subunit is mandatory forpathogenesis because of its vital role in binding to receptors of target cells [37–39]. The B complex binds to the intestinal epithelium and the A molecule thendetaches and enters the cell via endocytosis. The A molecule then goes ontoribosylating the Gs alpha-subunit of G proteins that results in constitutiveproduction of cAMP. The result is excretion of bicarbonate, chloride,potassium, and sodium ions as well as water from these cells [40]. Thus, theAB5 complex assembly is critical for pathogenesis. The virulence factors inboth O1/O139 and non-(O1/O139) strains have been identified [8,9,16,17,24,28,41]. It should be noted that information on the diarrheagenic potentialof non-(O1/O139) is limited. The effect of mutations in the toxin from allknown serogroups is not available. Therefore, it is of importance to describethe virulence factors in both O1/O139 and non-(O1/O139). This is possiblewith the help of known structural complexes available in Protein databank(PDB). A comprehensive analysis of the AB5 CT structures from PDBdescribing the nature of A and B5 interface has been documented elsewhere[42]. Here, we describe the significance of mutations in CT among serogroupsbased on their residue positional occurrence (either at solvent exposed orinterface regions of the AB5 complex).


Structural inferences for Cholera toxin mutations in Vibrio cholerae.

Shamini G, Ravichandran M, Sinnott JT, Somboonwit C, Sidhu HS, Shapshak P, Kangueane P - Bioinformation (2011)

Structural model of a cholera toxin (CT). CT is a hetero-hexamericcomplex (AB5) consisting of CTA (194 residues A1 and 46 residues A2) andCTB (103 residues) pentamer with D, E, F, G and H chains.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3064844&req=5

Figure 1: Structural model of a cholera toxin (CT). CT is a hetero-hexamericcomplex (AB5) consisting of CTA (194 residues A1 and 46 residues A2) andCTB (103 residues) pentamer with D, E, F, G and H chains.
Mentions: CT, also known as choleragen, is a hetero-hexameric AB5 complex in structure(Figure 1) [29–31] and is composed of an enzymatic A subunit (CTA) and acell targeting B subunit (CTB) [32–34]. The enzymatically activated A subunitcatalyzes adenylate cyclase to cause massive excretion of electrolytes frombowel [35,36]. However, the homo-pentamer B subunit is mandatory forpathogenesis because of its vital role in binding to receptors of target cells [37–39]. The B complex binds to the intestinal epithelium and the A molecule thendetaches and enters the cell via endocytosis. The A molecule then goes ontoribosylating the Gs alpha-subunit of G proteins that results in constitutiveproduction of cAMP. The result is excretion of bicarbonate, chloride,potassium, and sodium ions as well as water from these cells [40]. Thus, theAB5 complex assembly is critical for pathogenesis. The virulence factors inboth O1/O139 and non-(O1/O139) strains have been identified [8,9,16,17,24,28,41]. It should be noted that information on the diarrheagenic potentialof non-(O1/O139) is limited. The effect of mutations in the toxin from allknown serogroups is not available. Therefore, it is of importance to describethe virulence factors in both O1/O139 and non-(O1/O139). This is possiblewith the help of known structural complexes available in Protein databank(PDB). A comprehensive analysis of the AB5 CT structures from PDBdescribing the nature of A and B5 interface has been documented elsewhere[42]. Here, we describe the significance of mutations in CT among serogroupsbased on their residue positional occurrence (either at solvent exposed orinterface regions of the AB5 complex).

Bottom Line: The formation of the AB(5) complex involves inter-subunit residue-residue interactions at the protein-protein interfaces.Hence, these mutations, at the structurally relevant positions, are of importance for the understanding of pathogenesis by several serogroups.This is also of significance in the improvement of recombinant CT protein complex analogs for vaccine design and their use against multiple serogroups.

View Article: PubMed Central - PubMed

ABSTRACT
Cholera is a global disease that has persisted for millennia. The cholera toxin (CT) from Vibrio cholerae is responsible for the clinical symptoms of cholera. This toxin is a hetero-hexamer (AB(5)) complex consisting of a subunit A (CTA) with a pentamer (B(5)) of subunit B (CTB). The importance of the AB(5) complex for pathogenesis is established for the wild type O1 serogroup using known structural and functional data. However, its role is not yet documented in other known serogroups harboring sequence level residue mutations. The sequences for the toxin from different serogroups are available in GenBank (release 177). Sequence analysis reveals mutations at several sequence positions in the toxin across serogroups. Therefore, it is of interest to locate the position of these mutations in the AB(5) structure to infer complex assembly for its functional role in different serogroups. We show that mutations in the CTA are at the solvent exposed regions of the AB(5) complex, whereas those in the CTB are at the CTB/CTB interface of the homo-pentamer complex. Thus, the role of mutations at the CTB/CTB interface for B(5) complex assembly is implied. It is observed that these mutations are often non-synonymous (e.g. polar to non-polar or vice versa). The formation of the AB(5) complex involves inter-subunit residue-residue interactions at the protein-protein interfaces. Hence, these mutations, at the structurally relevant positions, are of importance for the understanding of pathogenesis by several serogroups. This is also of significance in the improvement of recombinant CT protein complex analogs for vaccine design and their use against multiple serogroups.

No MeSH data available.


Related in: MedlinePlus