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Originally published In Press as doi:10.1074/jbc.M111500200 on December 18, 2001

J. Biol. Chem., Vol. 277, Issue 10, 8217-8225, March 8, 2002
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The Prosequence of Human Lactase-Phlorizin Hydrolase Modulates the Folding of the Mature Enzyme*

Ralf Jacob, Karen Peters, and Hassan Y. NaimDagger

From the Department of Physiological Chemistry, School of Veterinary Medicine Hannover, Bünteweg 17, Hannover D-30559, Germany

The efficient transport of proteins along the secretory pathway requires that the polypeptide adopts a stably folded conformation to egress the endoplasmic reticulum (ER). The transport-competent precursor of the brush border enzyme LPH, pro-LPH, undergoes an intracellular cleavage process in the trans-Golgi network between Arg734 and Leu735 to yield LPHbeta initial. The role of the prodomain comprising the N-terminally located 734 amino acids of pro-LPH, LPHalpha , in the folding events of LPHbeta initial has been analyzed by the individual expression of both forms in COS-1 cells. Following synthesis at 37 °C LPHbeta initial acquires a misfolded and enzymatically inactive conformation that is degraded by trypsin. A temperature shift to 20 °C generates a stable, trypsin-resistant, and enzymatically active LPHbeta initial indicating that the individual expression of LPHbeta initial results in a temperature-sensitive conformation. This form interacts at non-permissive temperatures sequentially with the ER chaperones immunoglobulin-binding protein and calnexin resulting in an ER retention. The LPHalpha prodomain resides in the ER when individually expressed. It reveals compact structural features that are stabilized by disulfide bridges. LPHalpha and LPHbeta initial readily interact with each other upon coexpression, and this interaction appears to trigger the formation of a trypsin-resistant, correctly folded, enzymatically active, and transport-competent LPHbeta initial polypeptide. These data clearly demonstrate that the proregion of pro-LPH is an intramolecular chaperone that is critically essential in facilitating the folding of the intermediate form LPHbeta initial in the context of the pro-LPH polypeptide.

* This work was supported by Grant Na 331/1-2 from the Deutsche Forschungsgemeinschaft, Bonn, Germany and the Sonderforschungsbereich 280.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.

Dagger To whom correspondence should be addressed. Tel.: 49-511-953-8780; Fax: 49-511-953-8585; E-mail: Hassan.Naim@tiho-hannover.de.

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