REGULATION OF MEMBRANE FUSION

Emory University, Atlanta GA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term objective of this project has been to develop a detailed understanding of the process of cell entry of enveloped viruses, and mechanism of virus-induced cell fusion. We continued our studies with murine leukemia virus, a model oncogenic retrovirus, and parainfluenza virus, an important cause of respiratory disease. For the current reporting period the project focused on findings that the cytoplasmic domains of viral glycoproteins of two distinct virus families are able to regulate fusion activity. We continued our investigation of the role of cytoplasmic domains and structural features, which are important for their ability to modulate fusion activity. We determined the mechanism by which specific amino acid sequences in cytoplasmic tails of murine retrovirus Env proteins serve as potent inhibitors of virus-induced membrane fusion. To further define role of R peptide in regulation of fusion activity, we investigated its effects on stabilization of the oligomeric state of the Env protein. We have also continued to test the hypothesis that R peptide increases activation energy required for triggering conversion of Env from a metastable to a fusion-competent state. To investigate whether R peptide can affect a conformational change in external domain, we used influenza HA chimeric proteins having wild type or mutant MuLV Env cytoplasmic domains. We also determined if differences in interactions with cellular factors are observed with Env proteins having cytoplasmic domains that differentially affect fusion activity. We also have begun to investigate a newly characterized paramyxovirus, SER virus, which is closely related to SV5 in nucleotide and amino acid sequences. We have found that F protein of SER virus exhibits no cell fusion activity and that this is the result of an extended F cytoplasmic domain. We continued to define sequences in the SER cytoplasmic domain which modulate fusion activity, and possible mechanism involved in suppression of fusion activity by F cytoplasmic domain.