Judith White

..Clearly, highly divergent proteins have converged on the same overall strategy to mediate fusion, an essential step in the life cycle of every enveloped virus...

..Furthermore, recent studies have identified Niemann-Pick C1 (NPC1), a protein that resides deep in the endocytic pathway, as an important host factor in this process...

..Our findings also indicate that low pH and an additional endosomal factor (possibly reduction or possibly a process mimicked by reduction) act as fusion triggers...

..In this study we carried out a systematic analysis of the X. tropicalis genome and uncovered several interesting features of ADAM genes in this species...

..As ADAMs are also found in both vertebrates and invertebrates, some features of cell-cell fusion reactions may be conserved throughout the animal kingdom...

..Hence, ADAMs are emerging as key modulators of cell-cell and cell-matrix interactions. Important questions, including if and how ADAM adhesive domains promote ADAM protease function, are currently being addressed...

..But now a post-genomics approach has provided a powerful wedge into this difficult problem: a pheromone-induced multimembrane spanning protein has been identified as a key part of the mating machine...

..These and other results support a model in which CatB and CatL prime GP by generating a 19-kDa intermediate that can be acted upon by an as yet unidentified endosomal/lysosomal enzyme to trigger fusion...

..Possible roles for low pH at subsequent stages of viral entry are discussed...

..This work has therefore identified a single N-linked glycosylation site in the SU domain of EnvA that is critical for binding between EnvA and its receptor, Tva...

..These findings indicate that the cysteines flanking the internal fusion peptide of EnvA (and perhaps by analogy Ebola virus glycoprotein) are important for the foldback stage of the conformational changes that lead to membrane merger...

..A specific fixed angle boomerang structure is thus required to support membrane fusion...

..Low pH does not alter the off rate for the complex, further alter the secondary structure of SU-A, or induce measurable changes in tryptophan environment. The implications of these findings for fusion are discussed...

..Thus, anti-ASLV-SU-A mc8C5-4 proves to be a unique new immunoreagent that targets the receptor-binding site on a prototypical retroviral envelope...

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..These findings are likely relevant to other membrane-anchored cell surface proteases...

..These experiments support a model in which receptor interaction promotes formation of an envelope conformation in which the TM subunit is stably associated with its target membrane and is able to bind a C-terminal peptide...

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..Therefore, HA employs a 'leash in the groove,' rather than a helix-bundle, mechanism of membrane fusion...

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..Furthermore, with 293F cells the acquisition of EboV RBD binding paralleled cell spreading and did not require new mRNA or protein synthesis...

..Our data also indicate that the spring-loaded conformational change has another role beyond presenting the fusion peptide to the target membrane...

..These experiments suggest that ADAM2 contributes to RMS migration, possibly through cell-cell interactions that mediate the rapid migration of the neuroblasts to their endpoint...

..For example, the dual functions of ADAMs as both adhesion molecules and as proteases suggests that they may be key players in the de-adhesive, migratory, and re-adhesive activities involved in tumor metastasis. ..

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..The stage would then be set to screen for inhibitors of Ebola virus fusion and to test their efficacy in animal models. ..

..The project should also provide insights into pathologies that may involve other ADAMs, for examples metastasis and certain developmental abnormalities. ..

..In the case of HA, information on the fusion mechanism is now being coupled with structural information to rationally design fusion inhibitors. This strategy should be generalizable to other enveloped viruses. ..

..g. influenza, West Nile, and Ebola viruses). The proposed work will aid these important efforts. ..