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Journal of Virology, June 2000, p. 5509-5515, Vol. 74, No. 12
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Interactions between Hepatitis Delta Virus Proteins

Gloria Moraleda,1 Kate Dingle,1 Preetha Biswas,1 Jinhong Chang,1 Harmon Zuccola,2 James Hogle,2 and John Taylor1,*

Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111-2497,1 and Harvard Medical School, Boston, Massachusetts 021152

Received 15 December 1999/Accepted 9 March 2000

The 195- and 214-amino-acid (aa) forms of the delta protein (delta Ag-S and delta Ag-L, respectively) of hepatitis delta virus (HDV) differ only in the 19-aa C-terminal extension unique to delta Ag-L. delta Ag-S is needed for genome replication, while delta Ag-L is needed for particle assembly. These proteins share a region at aa 12 to 60, which mediates protein-protein interactions essential for HDV replication. H. Zuccola et al. (Structure 6:821-830, 1998) reported a crystal structure for a peptide spanning this region which demonstrates an antiparallel coiled-coil dimer interaction with the potential to form tetramers of dimers. Our studies tested whether predictions based on this structure could be extrapolated to conditions where the peptide was replaced by full-length delta Ag-S or delta Ag-L, and when the assays were not in vitro but in vivo. Nine amino acids that are conserved between several isolates of HDV and predicted to be important in multimerization were mutated to alanine on both delta Ag-S and delta Ag-L. We found that the predicted hierarchy of importance of these nine mutations correlated to a significant extent with the observed in vivo effects on the ability of these proteins to (i) support in trans the replication of the HDV genome when expressed on delta Ag-S and (ii) act as dominant-negative inhibitors of replication when expressed on delta Ag-L. We thus infer that these biological activities of delta Ag depend on ordered protein-protein interactions.

* Corresponding author. Mailing address: Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111-2497. Phone: (215) 728-2436. Fax: (215) 728-3105. E-mail: jm_taylor{at}fccc.edu.

Journal of Virology, June 2000, p. 5509-5515, Vol. 74, No. 12
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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