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Originally published In Press as doi:10.1074/jbc.M000431200 on May 31, 2000

J. Biol. Chem., Vol. 275, Issue 33, 25547-25555, August 18, 2000
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Pro-sterol Carrier Protein-2
ROLE OF THE N-TERMINAL PRESEQUENCE IN STRUCTURE, FUNCTION, AND PEROXISOMAL TARGETING*

Friedhelm SchroederDagger §, Andrey FrolovDagger , Olga Starodub, Barbara B. AtshavesDagger , William Russell||, Anca PetrescuDagger , Huan HuangDagger , Adalberto M. GallegosDagger , Avery McIntoshDagger , Dana TahotnaDagger , David H. Russell||, Jeffrey T. Billheimer**, Charles L. BaumDagger Dagger , and Ann B. Kier

From the Dagger  Department of Physiology and Pharmacology,  Department of Pathobiology, and || Department of Chemistry, Texas A & M University, College Station, Texas 77843-4466, the ** Cardiovascular Department, DuPont Merck Pharmaceutical Company, Experimental Station 400-3231, Wilmington, Delaware 19898-0400, and the Dagger Dagger  Department of Medicine, Clinical Nutrition Research Unit and Section of Gastroenterology, University of Chicago, Chicago, Illinois 60637

Although the 20-amino acid presequence present in 15-kDa pro-sterol carrier protein-2 (pro-SCP-2, the precursor of the mature 13-kDa SCP-2) alters the function of SCP-2 in lipid metabolism, the molecular basis for this effect is unresolved. The presequence dramatically altered SCP-2 structure as determined by circular dichroism, mass spectroscopy, and antibody accessibility such that pro-SCP-2 had 3-fold less alpha -helix, 7-fold more beta -structure, 6-fold more reactive C terminus to carboxypeptidase A, 2-fold less binding of anti-SCP-2, and did not enhance sterol transfer from plasma membranes. These differences were not due to protein stability since (i) the same concentration of guanidine hydrochloride was required for 50% unfolding, and (ii) the ligand binding sites displayed the same high affinity (nanomolar Kd values) in the order: cholesterol straight chain fatty acid > kinked chain fatty acid. Laser scanning confocal microscopy and double immunofluorescence demonstrated that pro-SCP-2 was more efficiently targeted to peroxisomes. Transfection of L-cells or McAR7777 hepatoma cells with cDNA encoding pro-SCP-2 resulted in 45% and 59% of SCP-2, respectively, colocalizing with the peroxisomal marker PMP70. In contrast, L-cells transfected with cDNA encoding SCP-2 exhibited 3-fold lower colocalization of SCP-2 with PMP70. In summary, the data suggest for the first time that the 20-amino acid presequence of pro-SCP-2 alters SCP-2 structure to facilitate peroxisomal targeting mediated by the C-terminal SKL peroxisomal targeting sequence.

* This work was supported in part by National Institutes of Health Grants GM 31561 and DK41402 (to F. S. and A. B. K.) and P30-ES0916 (to A. B. K. and D. H. R.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed. Tel.: 409-862-1433; Fax: 409-862-4929; E-mail: fschroeder@cvm.tamu.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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