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Volume 272, Number 8, Issue of February 21, 1997 pp. 5298-5304
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

In Vitro Assay and Characterization of the Farnesylation-dependent Prelamin A Endoprotease

(Received for publication, September 10, 1996, and in revised form, November 27, 1996)

Fusun Kilic Dagger , Marguerite B. Dalton § , Sarah K. Burrell , John P. Mayer , Scott D. Patterson par and Michael Sinensky Dagger

From the Dagger  Department of Biochemistry and Molecular Biology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614-0581, § Department of Physiology, University of Colorado Health Sciences Center, Denver, Colorado 80262,  Amgen Inc., Boulder, Colorado 80301, and par  Amgen Inc., Thousand Oaks, California 91320-1789

The 72-kDa nuclear lamina protein lamin A is synthesized as a 74-kDa farnesylated precursor. Conversion of this precursor to mature lamin A appears to be mediated by a specific endoprotease. Prior studies of overexpressed wild-type and mutant lamin A proteins in cultured cells have indicated that the precursor possesses the typical carboxyl-terminal S-farnesylated, cysteine methyl ester and that farnesylation is required for endoproteolysis to occur. In this report, we describe the synthesis of an S-farnesyl, cysteinyl methyl ester peptide corresponding to the carboxyl-terminal 18 amino acid residues of human prelamin A. This peptide acts as a substrate for the prelamin A endoprotease in vitro, with cleavage of the synthetic peptide at the expected site between Tyr657 and Leu658. Endoproteolytic cleavage requires the S-prenylated cysteine methyl ester and, in agreement with transfection studies, is more active with the farnesylated than geranylgeranylated cysteinyl substrate. N-Acetyl farnesyl methyl cysteine is shown to be a noncompetitive inhibitor of the enzyme. Taken together, these observations suggest that there is a specific farnesyl binding site on the enzyme which is not at the active site.


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