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Coils, Loops, and Fingers: Functional Motifs in Hantavirus Proteins
AuthorBoudreaux, Daniel Mark
AdvisorSt Jeor, Stephen C
Biochemistry and Molecular Biology
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New world hantaviruses are a threat as an emerging pathogen with the potential to cause outbreaks in rural regions remote from medical facilities. Medical authorities emphasize the need for preventative education programs and the development of antiviral drug treatments based on an understanding of the viral replication process. The virus is composed of three negative sense RNA genomic segments and four proteins; the RNA-dependent RNA polymerase (RdRP), glycoprotein Gn, glycoprotein Gc, and the nucleocapsid protein (Npro). This dissertation presents the structures of three motifs within hantavirus proteins as part of an effort to identify potential targets for antiviral drugs. 1) The NMR structure of the N-terminal region of Npro is described here to form a helical coiled-coil motif. Three acidic amino acids in this structure significantly contribute to the ability of Npro to self associate, an important process in viral replication. 2) The middle region of Npro is proposed at a low resolution to contain a helix-loop-helix motif which interacts with the cytoskeletal filament, vimentin. The Npro-vimentin interaction contributes to the proper trafficking of Npro through the cytoplasm. 3) The glycoprotein Gn contains an unusually long cytoplasmic tail with a conserved dual CCHC sequence. NMR resolution revealed that this sequence forms a zinc finger motif. The potential for this zinc finger to bind viral RNA was predicted by molecular modeling and molecular dynamic simulations. This interaction is thought to coordinate the packaging of each of the three viral genome segments. The presentation of these three structures contributes a better understanding of the physical properties of proteins involved in viral infections.