MACCHESS PROGRAM FOR MICROCRYSTALLOGRAPHY/MEMBRANE PROTEIN CRYSTALS

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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. 1.Structures of signaling complexes relevant to the actions of Cdc42: A major emphasis of our laboratory has been directed at understanding how GTP-binding proteins act as molecular switches in cell signaling pathways. One area of emphasis has been the Ras-related GTP-binding protein, Cdc42, which is one of the most highly conserved GTP-binding proteins from yeast to humans. Cdc42 has been shown to play a number of fundamentally important roles in cell biology. The hyper-activation of Cdc42 leads to malignant transformation. This involves a Cdc42-mediated signaling pathway that regulates the signaling lifetime and trafficking of growth factor receptors. In particular, the binding of activated Cdc42 to the g coatomer (gCOP) subunit, which is part of a multi-protein complex that coats trafficking vesicles, is essential for this trafficking function. We have been interested in determining how activated Cdc42 binds to the g-coatomer subunit and how g-coatomer engages associated subunits of the COPI complex to participate in the assembly of trafficking vesicles. Recently, we have published the structure for the amino-terminal half of the g-coatomer subunit to 2.1 angstrom resolution, based on data that we collected at MacCHESS (see Hoffman et al., below). This has allowed us to propose a model regarding how COPI trafficking vesicles assemble. Remarkably, it appears that the assembly of the COPI complex is similar to the assembly of the adaptor complexes that direct the formation of clathrin-coated vesicles and receptor endocytosis.