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Originally published In Press as doi:10.1074/jbc.M202837200 on June 27, 2002

J. Biol. Chem., Vol. 277, Issue 39, 36363-36372, September 27, 2002
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Modular Arrangement and Secretion of a Multidomain Serine Protease
EVIDENCE FOR INVOLVEMENT OF PROLINE-RICH REGION AND N-GLYCANS IN THE SECRETION PATHWAY*

Jing WangDagger §, Nguan Soon Tan||, Bow Ho**, and Jeak Ling DingDagger Dagger Dagger

From the Departments of Dagger  Biological Sciences and ** Microbiology, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore

The Limulus Factor C (FC), a multidomain glycoprotein that binds bacterial endotoxin with high affinity, belongs to the serine protease family of the complement and blood coagulation cascade. Here, we provide compelling evidence for the importance of modular arrangement and relevance of the proline-rich region (PRR) and N-glycosylation to the secretion and function of FC. We propose that PRR could be a universal conformational domain that regulates protein folding and targeting. FCs lacking PRR preceding the serine protease domain, were localized intracellularly. Misfolded conformers of the intracellular FCs were more susceptible to trypsin digestion. Glycosylation inhibition studies indicate that the presence but not the exact structure of the N-glycans affects the secretion of FC, although the complexity of glycosylation may influence its endotoxin-induced proteolytic cleavage with resultant enzymatic activity. Disruption of specific N-glycan sites at positions 740, 767, and 912, downstream of the PRR, at or near the serine protease domain, blocks its secretion. Co-expressed molecular chaperones like canine calnexin associates with glycosylated FCs to increase its solubility and secretion level but did not alter their expression profiles. Our results clearly demonstrate that the folding and secretion of a multidomain serine protease like FC are determined by its modular domain arrangement and site-specific N-glycans. The secreted FCs containing the N-terminal portion of FC are able to detect lipopolysaccharide with high sensitivity. We also identified the lectin-like and sushi 4 domains to contribute to the binding of lipopolysaccharide.


* This work was supported by National Science and Technology Board Grant NSTB/LS/99/004.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.

§ A postgraduate research scholar of the National University of Singapore.

Both authors contributed equally to this work.

|| Present address: Institut de Biologie Animale, Bâtiment de Biologie, Université de Lausanne, CH-1015 Lausanne, Switzerland.

Dagger Dagger To whom correspondence should be addressed: National University of Singapore, Marine Biotechnology Laboratory, Dept. of Biological Sciences, 14 Science Dr. 4, Singapore 117543, Singapore. Tel.: 65-8742776; Fax: 65-67792486; E-mail: dbsdjl@nus.edu.sg.


Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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