title: Prelamin A, Zmpste24, misshapen cell nuclei, and progeria--new evidence suggesting that protein farnesylation could be important for disease pathogenesis.
abstract: Prelamin A undergoes multistep processing to yield lamin A, a structural protein of the nuclear lamina. Prelamin A terminates with a CAAX motif, which triggers farnesylation of a C-terminal cysteine (the C of the CAAX motif), endoproteolytic release of the last three amino acids (the AAX), and methylation of the newly exposed farnesylcysteine residue. In addition, prelamin A is cleaved a second time, releasing 15 more residues from the C terminus (including the farnesylcysteine methyl ester), generating mature lamin A. This second cleavage step is carried out by an endoplasmic reticulum membrane protease, ZMPSTE24. Interest in the posttranslational processing of prelamin A has increased with the recognition that certain progeroid syndromes can be caused by mutations that lead to an accumulation of farnesyl-prelamin A. Recently, we showed that a key cellular phenotype of these progeroid disorders, misshapen cell nuclei, can be ameliorated by inhibitors of protein farnesylation, suggesting a potential strategy for treating these diseases. In this article, we review the posttranslational processing of prelamin A, describe several mouse models for progeroid syndromes, explain the mutations underlying several human progeroid syndromes, and summarize recent data showing that misshapen nuclei can be ameliorated by treating cells with protein farnesyltransferase inhibitors.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, University of California, Los Angeles, CA 90095, USA. sgyoung@mednet.ucla.edu
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
authors.forename: Loren G
authors.initials: LG
authors.lastname: Fong
authors.forename: Susan
authors.initials: S
authors.lastname: Michaelis
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D051231:Farnesyltranstransferase / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A; D008074:Lipoproteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011371:Progeria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011498:Protein Precursors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D034904:Lamin Type A; D008074:Lipoproteins; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A; D051231:Farnesyltranstransferase; D017346:Protein Serine-Threonine Kinases