STRUCTURAL AND FUNCTIONAL STUDIES OF P97

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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. We are pursuing structural and functional studies of p97 (also called VCP, valosin-containing protein; VAT in Archaebacteria; and cdc48 in yeast), a distant homolog of NSF. p97 has been implicated in postmitotic homotypic membrane fusion of the endoplasmic reticulum (ER) and of the Golgi apparatus, assembly and growth of the nucleus, apoptosis, and DNA replication. It is also involved in the ubiquitin-dependent degradation pathway, as well as the extraction of misfolded luminal and membrane proteins from the ER for cytosolic degradation. We recently determined the crystal structure of the biologically complete p97/VCP hexamer complexed with a mixture of ADP and ADP.AlFx using diffraction data collected at SSRL and APS. The MAD dataset collected at SSRL provided the key to solve the structure. The structure revealed the quarternary configuration of the individual domains and the connecting linkers. Our crystal structure represents a snapshot of p97/VCP as it proceeds through its nucleotide hydrolysis cycle. Our future plans include structural studies of complexes involving adapter proteins and substrates for p97/VCP, to elucidate the mechanism and biological role of p97/VCP.