S. typhi and typhoid toxin
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S. typhi and typhoid toxin
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[ID] => 554584
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[post_date] => 2024-12-23 17:56:49
[post_date_gmt] => 2024-12-23 22:56:49
[post_content] => Practice Passage (Question 1-5)
*This passage is the property of Khan Academy and has been reformatted into an AAMC-style interface in their entirety by MedLife Mastery. MedLife Mastery does not endorse and is not an affiliate of Khan Academy.
Typhoid fever is caused by the ingestion of food and water contaminated with the gram-negative bacterium Salmonella enterica serovar Typhi. Typhi bacteria are deadly because they produce a unique type of AB toxin. Typically AB toxins consist of two subunits: The “A” subunit is the active toxin and the “B” subunit binds to cell surface receptors, triggering endocytosis. Typhoid toxin is known as A2B5 because there are two different A units, CdtB and PltA, and a pentameric B subunit comprising 5 PltB peptides. In epithelial cells, typhoid toxin binds to podocalyxin-like protein 1 (PODXL) receptors.Researchers performed the following experiments to investigate S. typhi binding and toxicity.
Experiment 1
Researchers introduced shRNA (short hairpin RNA) and found that it decreased the toxin-binding ability of epithelial cells. In addition, they found that typhoid toxin binds to other cell types with the aid of carbohydrate moieties on the surface of glycoproteins. After removing the carbohydrates from the surfaces of the proteins, the binding ability of typhoid toxin was reduced.
Experiment 2
Researchers attempted to determine which subunit or subunits cause typhoid toxicity. For this investigation, they used mice, who do not have the receptors needed to initiate endogenous production of typhoid toxin but nevertheless respond to the toxin itself. Researchers injected experimental groups with high levels of normal typhoid toxin, CdtB only, PltA only, or both. Researchers used weight loss—a symptom of typhoid fever—as a gauge of toxicity levels. Results are shown in Figure 1.
Figure 1 Results of exposure to high levels of typhoid toxin, various typhoid toxin subunit proteins and to no toxin
Experiment 3
Researchers investigated the cell cycle status of cells treated with wild type S. Typhi or another variant of S. Typhi in which a disulfide bond in the junction between PltA and CdtB is broken. Cells in each stage of the cell cycle were quantified; results are shown in Figure 2.
Figure 2 Cell cycle profiles; peaks correspond to specified transitionary points
Sources: All figures information was adapted from J. Song, X. Gao, J.E. Galán Structure and function of the Salmonella Typhi chimaeric A2B5 typhoid toxin Nature, 499 (2013), pp. 350–354.
[post_title] => S. typhi and typhoid toxin
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[quiz_unique_key] => 602779517
[question] => Which subunit or subunits of the typhoid toxin is most likely the actual cause of typhoid fever?
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[answer] => 1
[description] => Reason for Correct Answer:
In Figure 1 the control cells not exposed to toxin have the same weight loss as those mice exposed to only PltA
Mice exposed to toxin CdtB have the same weight loss as mice exposed to both CdtB/PltA and the full typhoid toxin.
Since CdtB produces almost the same result by itself as it does combined with other proteins, CdtB is the most likely candidate for the toxin responsible for the symptoms of typhoid fever.
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[answers] => Array
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[0] => Array
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[each_answer] => A. CdtB
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[each_answer] => B. EPltA
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[each_answer] => C. CdtB and PltA
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[each_answer] => D. EThe entire toxin
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[1] => Array
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[quiz_unique_key] => 1403770772
[question] => What is the most likely explanation for how short hairpin RNAs (shRNA) reduce the toxicity of typhoid toxin?
[value] => Array
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[answer] => 3
[description] => Reason for Correct Answer:
shRNA are RNA strands produced inside of the cell. After a shRNA molecule is produced, the loop of the hairpin is cleaved and the two short strands of RNA can separate.
Once separated, the two short strands of RNA can hybridize to other strands of nucleic acid sequences that are in the cytosol.
The readily available strands of nucleic acid inside the cell are mRNAs. mRNA is abundant and also single stranded, so it will bind quickly to the short single strands of the shRNA molecule. Once the short strands of shRNA have hybridized to mRNA, the translation of the hybridized mRNA sequence into a peptide chain is blocked.
Of the answers given, it is therefore most likely that the shRNA contains a complementary sequence for the PODXL gene and therefore blocks PODXL receptors from ever being made on the rough ER by binding to the PODXL mRNA. Without PODXL receptors, cells will not bind with the typhoid toxin.
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[answers] => Array
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[0] => Array
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[each_answer] => A. The shRNA molecules block PODXL receptors on the cell surface.
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[1] => Array
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[each_answer] => B. The shRNA molecules bind with the “A” subunit of the typhoid toxin.
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[2] => Array
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[each_answer] => C. The shRNA molecules bind with the mRNA for PODXL receptors.
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[each_answer] => D. The shRNA molecules are inhibitors of PODXL gene transcription.
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[2] => Array
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[quiz_unique_key] => 1403770772
[question] => In which location do surface proteins usually undergo glycosylation?
[value] => Array
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[answer] => 4
[description] => Reason for Correct Answer:
Glycoproteins are mostly located on the outer plasma membrane surface of the cell.
For a protein to be located on the cell surface it had to undergo exocytosis via a vesicle.
Vesicles for surface proteins are formed on the rough endoplasmic reticulum.
All modifications to proteins will typically begin in the endoplasmic reticulum and continue in the Golgi body. Modifications are not made in the vesicle during exocytosis.
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[answers] => Array
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[0] => Array
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[each_answer] => A. In endosomes
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[each_answer] => B. In lysosomes
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[each_answer] => C. On the cell surface
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[3] => Array
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[each_answer] => D. In the endoplasmic reticulum
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[quiz_unique_key] => 1403770772
[question] => How does the breaking of the disulfide bond described in the passage alter the typhoid toxin?
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[answer] => 2
[description] => Reason for Correct Answer:
The passage states that the A subunits of the typhoid toxin compose the actual toxin and the B subunits bind to the cell. It also says the A unit consists of CdtB and PltA and B subunits consist of PltB peptides.
A disulfide bond between PltA and CdtB, as discussed in Experiment 3, is therefore not in the main site of binding (B subunit) but instead in the A subunit.
A broken disulfide bond (Cys mutation) at the junction between the two subunits could very well cause them to detach, disturbing quaternary structure. However, this could also affect tertiary structure by affecting the structure of each subunit.
Figure 2 shows the same cell cycle profile for cells infected with S. Typhi possessing the Cys mutation as it does for cells not infected (untreated). This suggests that the disulfide breaking mutation removes the toxicity of the bacterium, and this could very well be caused by disruption of the quaternary structure as the disulfide bond is between two subunits.
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[each_answer] => A. The broken disulfide bond alters the tertiary structure of the protein but does not inhibit receptor binding nor affect toxicity.
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[each_answer] => B. A broken disulfide bond alters the quaternary structure of the protein and eliminates toxicity of S. Typhi.
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[2] => Array
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[each_answer] => C. Because the disulfide bond is in the main site of attachment to cellular surface glycoproteins, breaking this bond interrupts cell binding.
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[each_answer] => D. The breaking of the disulfide bond decouples the toxic protein from the typhoid protein complex, yet the toxic protein itself retains its toxicity and causes cellular arrest.
)
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[quiz_unique_key] => 1403770772
[question] => Which conclusion is supported by the results of Experiment 3?
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[answer] => 2
[description] => Reason for Correct Answer:
Figure 1 shows the number of cells arrested at certain parts of the cell cycles. Here, you can compare untreated cells to cells treated with wild type S. typhi. Note that this doesn’t show anything about S. typhi cells themselves.
The figure is specifically showing the cells at certain cell cycle transitions or checkpoints – G0 to G1 and G2 to M phase.
The untreated group shows that most uninfected cells are stuck at the G0G1 transition. This means they are not entering G1 but are staying in G0.
The S. Typhi infected cells seem to be stuck at the G2M transitionary point or check point.
These means S. Typhi infected cells are arrested in the G2 phase of the cell cycle.
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[answers] => Array
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[0] => Array
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[each_answer] => A. The normal wild type (WT) of S. Typhi toxin causes more cells to progress through M phase, resulting in higher cell turnover.
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[each_answer] => B. The normal wild type (WT) of S. Typhi toxin causes cells to undergo cellular arrest, halting in the G2 phase of the cell cycle.
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[each_answer] => C. The untreated distribution of cells shows that most cells are arrested in the G1 phase of the cell cycle.
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[each_answer] => D. Few S. Typhi bacteria are arrested in the G₀ stage of the cell cycle.
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[554584|1] => A
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[554584|4] => B
[554584|5] => B
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Figure 1
Figure 2