Hutchinson-Gilford Progeria Syndrome (shortened to Progeria) is a genetic condit

Question

Hutchinson-Gilford Progeria Syndrome (shortened to Progeria) is a genetic condition characterized by premature aging and is uniformly fatal by the late teens. The primary gene mutated in Progeria is Lamin A, but the Progeria field is STILL trying to figure out how the molecular defect in Lamin A translates into disease symptoms. When scientists were first investigating Lamin A function, they used phospho-specific antibodies to discover that Lamin A was always phosphorylated at serine 22 during cell division in healthy cells.

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. How would farnesylation of a protein affect its localization in a cell?

Explanation / Answer

Answer:

Lamin A protein is localised to the cell nucleus and forms the nuclear lamina inside the nuclear membrane. Lamin A is expressed in the form of prelamin A and undergoes post-translational modifications. Prelamin A has CAAX as terminal amino acids sequence. This terminal triggers the farnesylation of the carboxy terminal of CAAX tetrapeptide by a cytosolic enzyme, protein farnesyltransferase. The farnesylated Prelamin A attaches with the Endoplasmic Reticulum. After farnesylation, the last three amino acids of Prelamin A are cleaved by an enzyme endoprotease. After the release of the terminal amino acids, methylation occurs in prelamin residue. Finally, farnesyl group is removed by ZMPSTE24 enzyme and forms mature Lamin A. This mature Lamin A is released from the endoplasmic reticulum into cytosol. The resulting protein Lamin A is no longer membrane-bound and carries out functions inside the nucleus normally.

In progeria, a mutation in the lamin A gene is one of the major cause. This leads to the defective Lamin A protein synthesis where farnesyl group remains attached with Prelamin A. This farnesylated form of prelamin A (progerin protein) is membrane-bound and attached with the nuclear membrane through endoplasmic reticulum. The binding for a longer period of time to nuclear membrane disturbs the nuclear lamina causing abnormal blebbing of the nuclear membrane, abnormal mitosis, genomic instability and thus premature senescence of cell.

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