This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The solution-phase protein motion that is part of a multi-component complex is rarely obvious from the high resolution three-dimensional structure. Protein function is intimately connected to dynamics and therefore knowledge of the frequency, range, and coordination of motion by supramolecular complexes is critical to understanding how they function. In this project, viruses are a paradigm for studying protein dynamics in supramolecular complexes. In the past year, significant steps have been made in Dr. Bothner's studies on the biophysical properties of virus particles. Systems currently under investigation include Hepatitis B virus, Adeno-associated virus, Canine Parvovirus, Cowpea Chlorotic Mottle Virus. A recent publication on Hepatitis B virus presents the first measurements of the rates and equilibria for protein motion in a megadalton complex. Breakthroughs have also been made in understanding how pH values, relevant to cell entry, modulates the stability and dynamics of parvoviruses. Through the use of a quartz crystal microbalance and atomic force microscopy the viscoelastic properties of a virus capsid in different conformation has been completed. Viruses are obligate cellular pathogens and therefore many cellular proteins are critical for viral infection, replication, and release from a host cell. Using proteomics-based approaches, Dr. Bothner's lab is seeking to identify cellular proteins that are hijacked by viruses during the infection process. The significance of this work is two fold; the basic biology of viruses can be elucidated and novel targets for antiviral agents will be identified. Dr. Bothner's work on murine norovirus infection of mouse RAW cells has lead to the identification of cysteine proteases, upstream of the mitochorndria that are involved with infection. Surprisingly, inhibition of caspases in general during infection, leads to rapid, non-apoptotic death.
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