The CFTR ion channel
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The CFTR ion channel
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[post_author] => 12815
[post_date] => 2024-12-23 17:47:44
[post_date_gmt] => 2024-12-23 22:47:44
[post_content] => Practice Passage (Question 1-6)
*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.
The cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane-bound glycoprotein with a 12-helix architecture comprising two pseudosymmetric transmembrane domains (MSD) and two nucleotide-binding domains (NBD), which bind and hydrolyze ATP. Between both NBD units is a single regulatory domain (R) that consists of many charged amino acids. The CFTR protein is predominantly expressed in the lungs, pancreas, sweat glands, intestine, liver, nasal mucosa, salivary glands, and reproductive tract.
Figure 1 Representation of the CFTR protein channel
Among human ABC proteins, CFTR is thought to be unique in that it has no active transport function, but instead acts as a phosphorylation-regulated, ATP-gated anion channel. Under normal conditions, CFTR works like a gate that is tightly coupled to ATPase cycles. The binding of ATP to the NBDs induces NBD dimerization – this results in the formation of a transmembrane domain cavity that opens towards the extracellular side to allow the selective flow of anions, such as chloride (Cl⁻⁻) and bicarbonate (HCO3⁻⁻). Particularly in the airway, CFTR regulates the local pH by allowing Cl⁻⁻ and HCO3⁻⁻ to flow out of the cell; in addition, it causes the epithelial sodium channel ENaC to transport sodium into the cell.
Cystic fibrosis (CF) is an autosomal recessive, multisystemic, and chronic disease that originates from pathogenic changes in the CFTR gene, located on the long arm of chromosome 7 (locus 7q.31). More than 2000 CFTR variants have been identified in CF patients, but the most common variant is a phenylalanine deletion at position 508 (p.F508del, ∆F508). The pathogenic variants and their effects have been grouped into several classes, as summarized in Table 1.
Table 1 Classification of CFTR gene mutations
Passage and figures adapted from Jaime A. López-Valdez et al, Cystic fibrosis: current concepts, https://www.bmhim.com/frame_esp.php?id=279
[post_title] => The CFTR ion channel
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[questions] => Array
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[question] => Which of the following is able to pass through the lipid bilayer the easiest without a transport protein?
[value] => Array
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[answer] => 3
[description] => Reason for Correct Answer:
Small, nonpolar molecules can diffuse across the plasma membrane easily.
Chloride ions are charged and cannot pass through the plasma membrane passively.
Cytokines are signaling molecules that bind to receptors on the plasma membrane surface, but are too large to cross the plasma membrane passively.
Oxygen gas is small and nonpolar, capable of passing through the bilayer. Although water can pass through, it passes very slowly.
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[answers] => Array
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[each_answer] => A. Chloride ions
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[each_answer] => B. Cytokines
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[each_answer] => C. Oxygen
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[each_answer] => D. Water
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[1] => Array
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[quiz_unique_key] => 1403770772
[question] => Which is LEAST likely true regarding CF and the CFTR protein?
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[answer] => 3
[description] => Reason for Correct Answer:
All the relevant information is in Paragraph 2, which describes the CFTR protein.
Paragraph 2 states that the CFTR protein does not actually operate by active transport. By definition, then, it must be moving chloride passively down its concentration gradient, as in Choice D.
The buildup of chloride in the cell resulting from CFTR defects would increase the number of ions inside the cell, thus drawing water into the cell (increasing osmosis into the cell), as in Choice B.
Paragraph 2 also says that CFTR “causes the epithelial sodium channel ENaC to transport sodium into the cell.” This means that defects in the CFTR protein can cause a buildup of sodium outside the cell, especially in places like sweat glands where the passage says CFTR is very active. This is why the sweat test for elevated sodium, as in Choice A, can help identify individuals with CF.
Paragraph 2 also states that “particularly in the airway, CFTR regulates the local pH by allowing Cl− and HCO3− (bicarb, a base) to flow out of the cell,” which means that CFTR makes the surface of the airway more basic, and that CFTR dysfunction in CF patients would increase airway acidity.
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[each_answer] => A. A salty sweat test (increased sodium in sweat) can be useful for identifying individuals with CF.
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[each_answer] => B. Decreased activity of the CFTR protein tends to draw water into the cell.
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[each_answer] => C. The airway surface in CF patients is several times more basic.
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[each_answer] => D. CFTR moves chloride down its concentration gradient.
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[2] => Array
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[quiz_unique_key] => 1403770772
[question] => Which set of amino acids is most likely to be found in a region of MSD2 protein domain that resides within the membrane but does not make contact with the chloride channel?
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[answer] => 2
[description] => Reason for Correct Answer:
The MSD2 protein domain is a transmembrane domain.
Transmembrane domains are regions of membrane proteins that span the lipid bilayer of the cell membrane. These regions are composed mainly of hydrophobic amino acids that interact with the hydrophobic core of the lipid bilayer, allowing the protein to embed within the membrane.
Here is a list of the amino acids and their symbols:
https://commons.wikimedia.org/wiki/File:Amino_Acids-wide.svg
Among the options provided, the set of amino acids “LLMVVPLIG” is the most likely to be found in transmembrane domain – in a part that does not contact the chloride channel – because it consists almost exclusively of hydrophobic amino acids (L = leucine, M = methioine, V = valine, P = proline, I = isoleucine), with G = glycine, which only has -H as an R group.
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[answers] => Array
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[each_answer] => A. KREHFGTYW
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[each_answer] => B. LLMVVPLIG
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[2] => Array
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[each_answer] => C. QRNDKSHEA
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[each_answer] => D. NCGTPWYNQ
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[quiz_unique_key] => 1403770772
[question] => Which graph most closely represents the relative chloride conductance of mucosal membranes isolated from individuals with normal CFTR protein expression versus those who are homozygous for one particular class of mutation?
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[answer] => 1
[description] => Reason for Correct Answer:
Table 1 describes the CFTR defects that result from each class of mutation.
Keep in mind that more functional CFTR reaching the membrane corresponds to more chloride conductance.
Class III–VI mutations result in either a decrease in ion transport or a decrease in the amount of CFTR protein present in the membrane. Both of these situations would result in some chloride conductance, but less than that of a normal CFTR-containing membrane.
Class I, II, and VII mutations result in CFTR not being produced or not reaching the membrane.
This would result in a more severe reduction of chloride conductance with Class I, II, and VII mutations, as in Choice A.
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[0] => Array
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[each_answer] => A.
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[each_answer] => B.
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[2] => Array
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[each_answer] => C.
)
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[each_answer] => D.
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[quiz_unique_key] => 1403770772
[question] => The most common CF-causing mutation is a deletion of three nucleotides at position 508 of the CFTR protein, which results in a loss of phenylalanine from the NBD1 domain. What is the most likely reason that CFTR can no longer function?
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[answer] => 2
[description] => Reason for Correct Answer:
The table shows that the F508del results in “traffic defects: CFTR protein is created but cannot reach the cell surface.”
The deletion of phenylalanine would not result in a truncated protein or a frameshift mutation, only in the loss of the single amino acid.
Although the F508del is in a nuclear binding domain, it prevents the CFTR protein from even reaching the membrane, so we can’t attribute the effect of the mutation to an issue with nucleotide binding.
The effect of the mutation would be explained by improper protein folding, resulting in a misfolded protein that is retained in the ER, instead of being transported to the Golgi and then to the cell membrane.
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[each_answer] => A. This deletion results in a frameshift mutation so the rest of the protein is not translated properly and the protein is degraded.
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[each_answer] => B. This deletion results in a protein that is unable to fold correctly, resulting in an unstable protein that is retained in the ER.
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[each_answer] => C. This deletion results in a single amino acid change that impairs the protein’s ability to interact with nucleotides.
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[each_answer] => D. This deletion results in a truncated protein that is not able to function normally.
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[quiz_unique_key] => 1115843717
[question] => Read-through agents are a class of drugs that are being explored as potential treatments for certain genetic diseases. These drugs allow premature stop codons to be ‘read through’ by promoting the insertion of amino acids by near-cognate tRNA anticodons. Which of the following classes of cystic fibrosis would most likely be amenable to treatment with read-through agents?
[value] => Array
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[answer] => 1
[description] => Reason for Correct Answer:
Premature stop codons are generated by nonsense mutations; this is when a mutation gives rise to a DNA codon that codes for a stop codon, rather than an amino acid.
Read-through agents prevent a truncated protein from being synthesized by allowing the premature stop codon to be ‘filled’ with another amino acid.
The classes of cystic fibrosis that are caused by an amino acid deletion (e.g. pF508del) or substitution (e.g. p.G551D) do not involve a premature stop codon – in these classes, the resulting proteins are full length (or close to full length), but have modified functions.
The only class that is caused by premature stop codons is Class I. Here, nonsense mutations (e.g. pG542X) prevent the synthesis of protein or cause the synthesis of truncated proteins.
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[each_answer] => A. Class I
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[each_answer] => B. Class II
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[each_answer] => C. Class III
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[each_answer] => D. Class IV
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[554020|4] => A
[554020|5] => B
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Figure 1
Table 1
