Lamin A processing pathway (Homo sapiens)

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All lamins, except lamin C, contain a CaaX tail. This tail is comprised of respectively cysteine, two aliphatic amino acids and any amino acid with a COOH-terminal (variable). Aliphatic amino acids are nonpolar and hydrophobic and include glycine, alanine, valine, leucine and isoleucine. This structure acts as recognition point for a sequence of modifications. First the terminal cysteine is farnesylated by farnesyl transferase, where a isoprenyl group is added to the cysteine residue -also called isoprenylation. This is followed by proteolytic cleavage of the aaX part by Zmpste24 and methylation of cysteine. Isoprenylation and methylation are both necessary for the localization of lamin A and B-type lamins in to the INM. Until this point processing of lamin A and type-B lamins is similar. While in type-B lamins the isoprenyl group remains attached to the cysteine, lamin A has a second cleavage site to cleave off an additional 15 amino acids upstream of the cysteine. This cleavage is also done by Zmpste24 and takes place at INM. When these 15 amino acids, 18 in total including aaX, are cleaved off mature lamin A is produced (1,2).