A DRAMATIC SHIFT IN THE TRANSMEMBRANE TOPOLOGY OF A VIRAL ENVELOPE GLYCOPROTEIN ACCOMPANIES HEPATITIS-B VIRAL MORPHOGENESIS

The envelope of hepatitis B virus contains three related glycoproteins (termed L, M and S) produced by alternative translation initiation in a single coding region. The smallest of these, the S protein, is a 24 kDa glycoprotein with multiple transmembrane domains. The M and L pro teins contain the entire S domain at their C-termini, but harbor at th eir N-termini additional (preS) domains of 55 or 174 amino acids, resp ectively. Most of these preS residues are displayed on the surface of mature virions and hence would be expected to be translocated into the endoplasmic reticulum (ER) lumen during biosynthesis. Using a coupled , in vitro translation/translocation system we now demonstrate that, c ontrary to expectation, virtually all preS residues of the L protein a re cytoplasmically disposed in the initial translocation product. This includes some preS sequences which in the M protein are indeed transl ocated into the ER lumen. Since preS sequences are found on the extern al surface of the virion envelope, our results indicate that during or following budding a dramatic reorganization of either the envelope pr oteins or the lipid bilayer (or both components) must occur to allow s urface display of these sequences. These findings imply that some memb rane budding events can have remarkable and previously unsuspected top ological consequences.