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Journal of Virology, June 2002, p. 5480-5491, Vol. 76, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.11.5480-5491.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Folding and Dimerization of Tick-Borne Encephalitis Virus Envelope Proteins prM and E in the Endoplasmic Reticulum

Ivo C. Lorenz,1 Steven L. Allison,2 Franz X. Heinz,2 and Ari Helenius1*

Institute of Biochemistry, Swiss Federal Institute of Technology, CH-8093 Zürich, Switzerland,1 Institute of Virology, University of Vienna, A-1095 Vienna, Austria2

Received 10 October 2001/ Accepted 7 March 2002

Flavivirus envelope proteins are synthesized as part of large polyproteins that are co- and posttranslationally cleaved into their individual chains. To investigate whether the interaction of neighboring proteins within the precursor protein is required to ensure proper maturation of the individual components, we have analyzed the folding of the flavivirus tick-borne encephalitis (TBE) virus envelope glycoproteins prM and E by using a recombinant plasmid expression system and virus-infected cells. When expressed in their polyprotein context, prM and E achieved their native folded structures with half-times of approximately 4 min for prM and about 15 min for E. They formed heterodimeric complexes within a few minutes after synthesis that were required for the final folding of E but not for that of prM. Heterodimers could also be formed in trans when these proteins were coexpressed from separate constructs. When expressed without prM, E could form disulfide bonds but did not express a specific conformational epitope and remained sensitive to reduction by dithiothreitol. This is consistent with a chaperone-like role for prM in the folding of E. PrM was able to achieve its native folded structure without coexpression of E, but signal sequence cleavage at the N terminus was delayed. Our results show that prM is an especially rapidly folding viral glycoprotein, that polyprotein cleavage and folding of the TBE virus envelope proteins occurs in a coordinated sequence of processing steps, and that proper and efficient maturation of prM and E can only be achieved by cosynthesis of these two proteins.

* Corresponding author. Mailing address: Institute of Biochemistry, Swiss Federal Institute of Technology, ETH Hoenggerberg, HPM E6.3, CH-8093 Zürich, Switzerland. Phone: 41-1-6326817. Fax: 41-1-6321269. E-mail: ari.helenius{at}bc.biol.ethz.ch.

Journal of Virology, June 2002, p. 5480-5491, Vol. 76, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.11.5480-5491.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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