Stephen C. Harrison
We are structural biologists concerned with the organization and dynamics of macromolecular assemblies. We ask the following kinds of questions. (1) How do viruses assemble and how do they enter and exit the cells they infect? (2) Can we combine our understanding of virus structure and entry with contemporary methods for probing the human immune response, to arrive at novel strategies for vaccine design? (3) What is the molecular architecture of a kinetochore? How does this architecture embody its required mechanical and signal-transducing properties? We are also interested ih the methodological issue of how to relate high-resolution structures, especially from cryo-EM, to time-series data from live-cell fluorescence imaging.
(1) We are particularly interested in determining the molecular events that accompany penetration of a virus into a cell – a process that takes the form of membrane fusion in the case of enveloped viruses and of membrane perforation in the case of nonenveloped viruses. Structural analyses of viruses and viral proteins are at the core of our efforts to understand these steps. Much of our recent work has focused on the double-stranded RNA viruses and on the proteins that carry out the membrane penetration step. Another component of our research seeks to extend our structural understanding of membrane fusion as facilitated by viral fusion proteins.
(2) Viral structural proteins are also the principal antigens recognized by protective antibodies. New methods for analyzing the human B-cell repertoire allow us to reconstruct stages of the antibody response to vaccination or infection, in particular by influenza virus, and to determine the structural correlates of the process of antibody affinity maturation. Much of our work in this area has been in collaboration with the Duke Human Vaccine Institute.
(3) Kinetochores link chromosomal centromeres to microtubules of the mitotic spindle. The kinetochores of budding yeast are assemblies of at least 50 protein species, nearly all of which have homologs in higher eukaryotes. These proteins come together into well-defined complexes that have an elaborate network of regulated contacts with each other, with centromeric chromatin, and with microtubules. We have undertaken to build up a three-dimensional picture of a yeast kinetochore, starting with efforts to crystallize some of its constituent protein complexes but now focused almost entirely on larger structures studied by cryo-EM.
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