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Volume 271, Number 31, Issue of August 2, 1996 pp. 18912-18919
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Biosynthesis of Surfactant Protein D
CONTRIBUTIONS OF CONSERVED NH₂-TERMINAL CYSTEINE RESIDUES AND COLLAGEN HELIX FORMATION TO ASSEMBLY AND SECRETION

(Received for publication, January 19, 1996, and in revised form, April 23, 1996)

From the Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110

Surfactant protein D (SP-D) is preferentially secreted as dodecamers consisting of four collagenous trimers cross-linked by disulfide bonds. In these studies, we examined the biosynthesis of wild-type rat SP-D (RrSP-D) and selected mutants by stably transfected CHO-K1 cells to determine the roles of a conserved N-linked oligosaccharide, the collagen helix, and interchain disulfide bonds in SP-D assembly and secretion. The major intracellular form of RrSP-D accumulated in the RER as complexes containing up to four trimeric subunits. Disulfide cross-link formation and RrSP-D secretion were selectively inhibited by 2,2-dipyridyl, an inhibitor of prolyl and lysyl hydroxylase, and by 2 mM dithiothreitol, but unaffected by tunicamycin or elimination of the consensus sequence for glycosylation at Asn⁷⁰. Although mutants with serine substituted for Cys¹⁵ and Cys²⁰ (RrSP-Dser15/20) are secreted as trimeric subunits, proteins with single cysteine substitutions were retained in the cell. Surprisingly, the secretion of RrSP-Dser15/20 was unaffected by 2,2-dipyridyl. These studies strongly suggest that the most important and rate-limiting step for the secretion of SP-D involves the association of cross-linked trimeric subunits to form dodecamers stabilized by specific inter-subunit disulfide cross-links. Interference with collagen helix formation prevents secretion by interfering with efficient disulfide cross-linking of the NH₂-terminal domain.

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