It is known that Lamin A normally gets “farnesylated” after it is translated. Fa

Question

It is known that Lamin A normally gets “farnesylated” after it is translated. Farnesylation occurs when a farnesyltransferase protein adds a hydrophobic lipid tail (called a farnesyl group) to the lamin protein. While Lamin A gets farnesylated to achieve its initial sub-cellular localization, the farnesyl group is later cleaved by a protease in order for Lamin A to function properly. However, it has recently been discovered that, in Progeria, the cleavage of the farnesyl group does not occur, and thus, the farnesyl group is retained. One downstream effect of the farnesyl group is that its presence appears to block phosphorylation of Lamin A on serine.

Researchers wondered whether inhibiting farnesylation in the first place would make a difference in Lamin A phosphorylation. lonafarnib is a small farnesyl transferase inhibitor. When they added this inhibitor, then performed a Western blot for phosphorylated Lamin A and total Lamin A, for several experimental conditions, they observed the following results. Healthy Progeria Progeria +inhibito Lamin A S22D mutant P- Lamin A total- Lamin A g) Based on the results of this blot, can Lamin A get phosphorylated after farnesyl transferase inhibition? (2 pts) Yes Unclear No h) Given this result, what effect would farnesyltransferase inhibitors have on accumulation of Lamin A in the cells of progeria patients? (4 pts) reduce accumulation no effect increase accumulation i Would replacing Lamin A with a serine-to-aspartate mutant version (in cells from healthy patients) lead to more or less accumulation of Lamin A at its normal sub-cellular localization? (4 pts) less accumulation no effect more accumulation

Explanation / Answer

g) Lamin A gets phosphorylated after the farnesyl transferase inhibitor. In lane 3 where inhibitor is added wre can see two bands, one of which corresponds to phosphorylated Lamin A when compared with healthy individuals.

h) The farnesyl transferase inhibition results in the phosphorylation and thus normal functioning of Lamin A. Since in progeria patients, farnesyl group causes accumulation of Lamin A at its target site, therefore, the inhibitor will reduce its accumulation

i) in lane 4… the mutant version of Lamin A seems to accumulate as we saw a single band corresponding to total Lamin A as well as we didn't see a band corresponding to phosphorylated Lamin A

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