You are working in a biotech company that has discovered a small-molecule drug called H5434. H5434 binds to LDL receptors when they are bound to cholesterol. H5434 binding does not alter the conformation of the LDL receptor's intracellular domain

Question

Interestingly, in vitro experiments demonstrate that addition of H5434 increases the affinity of LDL for cholesterol and prevents cholesterol from dissociating from the LDL receptor even in acidic conditions. Which of the following is a reasonable prediction of what may happen when you add H5434 to cells?
(a) Cytosolic cholesterol levels will remain unchanged relative to normal cells.
(b) Cytosolic cholesterol levels will decrease relative to normal cells.
(c) The LDL receptor will remain on the plasma membrane.
(d) The uncoating of vesicles will not occur.

Answer 1

(b) Normally, cholesterol dissociates from the LDL receptor in the acidic environment of the endosomes and is released into the cytosol. If the drug prevents cholesterol from dissociating from the LDL receptor in acidic conditions, cholesterol may not become released into the cytosol, and thus cytosolic cholesterol levels are likely to decrease relative to those in normal cells. There is no reason to believe that the LDL receptor will remain on the plasma membrane [choice (c)], because the cytosolic region of the receptor is not directly altered by the drug. Vesicle uncoating is also unlikely to be altered [choice (d)], because this occurs after vesicles are pinched off from the membrane.