Description

Lamin A is translated as a precursor protein harbouring a C-terminus CaaX sequence, which is typical of farnesylated proteins. In prelamin A, the CaaX sequence is made up of cysteine, serine, isoleucine and methionine (CSIM). Methionine directs farnesylation at the cysteine residue by the enzyme protein farnesyltransferase. Following cysteine farnesylation, the SIM sequence is removed by the endoprotease ZMPSTE24. This proteolytic reaction is thought to be also carried out by the endoprotease RCE1, which could replace ZMPSTE24 . The cysteine residue is then methylated by the methyltransferase Icmt and a final proteolytic cleavage, performed by ZMPSTE24, removes a further 15 C-terminal residues to produce mature lamin A. Thus, at least four prelamin A species are transiently formed during prelamin A maturation, including unprocessed prelamin A, which is not farnesylated (preLA-CSIM), farnesylated full-length prelamin A (preLA- farnesyl-CSIM), farnesylated prelamin A lacking the SIM sequence (preLA-farnesyl-C), and carboxymethylated-farnesylated prelamin A (preLA-farnesyl-C-CH3). Mutations in lamin A produce a range of diseases that have collectively been referred to as `laminopathies’ . Two progeroid (premature aging) syndromes, Hutchinson-Gilford progeria (HGPS)and restrictive dermopathy (RD), are laminopathies that arise through defects in maturation of the lamin A precursor, prelamin A. Mandibuloacral dysplasia (MAD), which can be considered a milder form of RD, also results in accumulation of the lamin A precursor. By contrast, the majority of laminopathies are due to point mutations in the A/C lamins; these exhibit a multitude of phenotypes depending on the site of the mutation .