Grants and Contracts Details
Description
The Paramyxoviridae are a diverse family of enveloped viruses, with homologous members such as simian
virus 5 (SV5) and mumps virus and newly emerged and disparate members such as Hendra and Nipah
viruses. Paramyxoviruses possess a surface glycoprotein, the fusion (F) protein, which promotes fusion
between the viral envelope or virus-infected cell membrane and a target cell membrane. While several
domains within the F protein have identified roles in membrane fusion, the majority of the protein has no
defined function. Our central hypothesis is that conserved regions among diverse members of the
Paramyxoviridae F proteins have important conserved functions, either in the folding of fusion proteins or in
aiding F-mediated fusion events. Sequence alignment of F proteins from disparate members of the
Paramyxovirus family and analysis by the Block Maker program were used to identify three blocks of
conserved amino acid sequence. Two of the identified blocks of conservation (CBF1 and CBF2) are in regions
which currently have no known function. The proposed research will examine the function of conserved
residues within paramyxovirus fusion proteins utilizing site-directed mutagenesis and transient expression
systems, along with metabolic labeling and immunoprecipitation or fusion assays. Our initial studies found that
point mutations in CBF1 led to defects in homotrimerization, an event that is essential for the fusogenic activity
of the F protein. These results both provide the first identification of a region important for trimer formation of
paramyxovirus F proteins, and support our hypothesis that conserved domains playa critical role in folding or
function. Specific Aim 1 will analyze the effects of mutations in the second conserved block of unknown
function, CBF2. Experiments in Specific Aim 2 will address the function of residues in the fusion peptide that
are modified in the newly emerged paramyxovirus Hendra as compared to previously characterized members
of the family. Accomplishing these goals will provide new insight into the role of these sequences in the folding
of, or fusion promotion by, these critical viral proteins. These studies should also shed light on the folding of
glycoproteins in the endoplasmic reticulum and the basic process of membrane fusion. In addition, domains
demonstrated to be critical in membrane fusion promotion could serve as targets for antiviral therapy.
Status | Finished |
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Effective start/end date | 7/1/04 → 6/30/06 |
Funding
- American Heart Association Ohio Valley Affiliate: $36,000.00
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