Hepatitis B surface antigen assembles in a post-ER, pre-Golgi compartment

We felt that the consensus view led to a paradox since it posits that the complex disulphide crosslinks which stabilize the secreted particle are formed in the ER and hence in the presence of high levels of PDI. The current model for intracellular disulphide bond formation is based on studies of intramolecular disulphide pairing in soluble monomeric proteins (Freedman and Hillson, 1980; Creighton, 1984; Freedman, 1984) . The rate limiting step in the folding of many disulphide containing proteins is the exchange of disulphide bonds to generate the final, lowest free energy arrangement of the native state. Protein disulphide isomerase (PDI), an abundant, soluble resident protein of the ER, accelerates this process by catalyzing disulphide bond exchange and so causes dissociation of disulphide-linked aggregates and allows refolding of proteins to their native, properly disulphide-linked conformation. Two classes of disulphide bonds can be distinguished operationally in our studies. The first class comprises the crosslinks within an HBsAg dimer. We hypothesized that the formation of these bonds would be promoted by PDI since they are analogous to the bonds linking small oligomers such as influenza haemagglutinin. We shall refer to this class as dimer crosslinks. The second set of crosslinks are those that bind dimers together to form the highly crosslinked oligomer. We felt that it was unlikely that this second class would be stable in the presence of PDI since they resemble the aggregated crosslinks resolved by this enzyme. The formation of these oligomer crosslinks cannot be completed without particle assembly since they stabilize the oligomeric lipoprotein particle.