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A more recent version of this article appeared on December 1, 2005

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J. Lipid Res., doi:10.1194/jlr.R500011-JLR200
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Submitted on September 14, 2005
Accepted on October 4, 2005

Prelamin A, Zmpste24, misshapen cell nuclei, and progeria - New evidence suggesting that protein farnesylation could be important for disease pathogenesis

Stephen G. Young, Loren G. Fong, and Susan Michaelis

Dept of Internal Medicine/Div of Cardiology, UCLA, Los Angeles, CA 90095

Corresponding Author: sgyoung{at}mednet.ucla.edu

Prelamin A undergoes multi-step processing to yield lamin A, a structural protein of the nuclear lamina. Prelamin A terminates with a CAAX motif, which triggers farnesylation of a carboxyl-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 carboxyl terminus (including the farnesylcysteine methyl ester), generating mature lamin A. This second cleavage step is carried out by an ER 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 have shown 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.


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