| Structure 1998 Jul 15;6(7):821-830
Structural basis of the oligomerization of hepatitis
delta antigen.
Zuccola HJ, Rozzelle JE, Lemon SM, Erickson BW, Hogle JM
Department of Biological Chemistry and Molecular Pharmacology, Harvard
Medical School, Boston, MA 02115, USA. harmon@dag.med.harvard.edu
BACKGROUND:
The Hepatitis D virus (HDV) is a small satellite virus of Hepatitis B
virus (HBV). Coinfection with HBV and HDV causes severe liver disease
in humans. The small 195 amino-acid form of the hepatitis delta antigen
(HDAg) functions as a trans activator of HDV replication. A larger form
of the protein containing a 19 amino acid C-terminal extension inhibits
viral replication. Both of these functions are mediated in part by a stretch
of amino acids predicted to form a coiled coil (residues 13-48) that is
common to both forms. It is believed that HDAg forms dimers and higher
ordered structures through this coiled-coil region.
RESULTS:
The high-resolution crystal structure of a synthetic peptide corresponding
to residues 12 to 60 of HDAg has been solved. The peptide forms an antiparallel
coiled coil, with hydrophobic residues near the termini of each peptide
forming an extensive hydrophobic core with residues C-terminal to the
coiled-coil domain in the dimer protein. The structure shows how HDAg
forms dimers, but also shows the dimers forming an octamer that forms
a 50 A ring lined with basic sidechains. This is confirmed by cross-linking
studies of full-length recombinant small HDAg.
CONCLUSIONS:
HDAg dimerizes through an antiparallel coiled coil. Dimers then associate
further to form octamers through residues in the coiled-coil domain and
residues C-terminal to this region. Our findings suggest that the structure
of HDAg represents a previously unseen organization of a nucleocapsid
protein and raise the possibility that the N terminus may play a role
in binding the viral RNA.
PMID: 9687364, UI: 98362586
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