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J. Biol. Chem., Vol. 278, Issue 48, 47979-47986, November 28, 2003

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Processing of Surfactant Protein C Requires a Type II Transmembrane Topology Directed by Juxtamembrane Positively Charged Residues^*

Surafel Mulugeta and Michael F. Beers

From the Lung Epithelial Cell Biology Laboratories, Pulmonary and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4318

Surfactant protein C (SP-C) is a lung-specific protein that is synthesized as a 21-kDa integral membrane propeptide (pro-SP-C) and proteolytically processed to a 3.7-kDa secretory product. Previous studies have shown that palmitoylation of pro-SP-C is dependent on two N-terminal juxtamembrane positively charged residues. We hypothesized that these residues influence modification of pro-SP-C by directing transmembrane orientation. Double substitution mutation of these juxtaposed residues from positive to neutral charged species resulted in complete reversal of transmembrane orientation of pro-SP-C and total abrogation of post-translational processing. Mutation of a single residue resulted in mixed orientation. Protein trafficking studies in A549 cells showed that while the double mutant was retained in the endoplasmic reticulum, single mutants produced a mixed pattern of both endoplasmic reticulum (double mutant-like) and vesicular (wild type-like) expression. Our study demonstrates the crucial role juxtamembrane positively charged residues play in establishing membrane topology and their influence on the trafficking and processing of pro-SP-C. Moreover this study provides a likely precedent for a mechanism in disorders associated with mutations in the membrane-flanking region of integral membrane proteins.

Received for publication, July 28, 2003 , and in revised form, August 14, 2003.

^* This work was supported by National Institutes of Health Grants HL-19737, P50-HL56401, and HL74064 (to M. F. B.) and American Lung Association Dalsemer Research Grant DA-188-N (to S. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This 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: Pulmonary and Critical Care Division, University of Pennsylvania, Abramson Research Center, Room 1015 Hb, 3615 Civic Center Blvd., Philadelphia, PA 19104-4318. Tel.: 215-746-2920; Fax: 215-573-4469; E-mail: mulugeta{at}mail.med.upenn.edu.

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