We want to understand how complex macromolecular assemblies within cells are built, maintained, and remodeled at the right place and time. For most such assemblies, form is clearly critical for cellular function; consider, as examples, the barrel-like stacks of oligomeric rings found in nuclear pores and proteasomes. Numerous diseases, among them neurodegenerative disorders and systemic amyloidoses, arise from inappropriate folding of, or interactions between, protein subunits. Exactly what regulates higher-order assembly in normal and disease states is largely unknown, reflecting a gap between what traditional biochemical and cell biological approaches can tell us. We use new tools and approaches that fill this gap and enable the identification of molecular mechanisms by which functional higher-order structures are assembled from protein subunits and maintained or modified through cell division and differentiation.
Members of the septin family of proteins are found in nearly every eukaryote, typically as hetero-oligomeric complexes, the proper organization of which is required for their function. Although the mechanistic details of their roles remain largely unknown, septins participate in a variety of cellular processes, generally involving plasma membrane remodeling. Mutation or misregulation that upsets the stoichiometry of septin hetero-oligomers is a common feature of septin-associated human diseases, which include cancer, male infertility, and hereditary neuropathies. In budding yeast, where septins were first identified, hetero-octamers – whose subunit composition is strikingly similar to those within human septin complexes – polymerize into filaments arrayed at sites of cell division and morphogenesis. Septin-containing cellular structures in dividing and differentiating cells are dynamic, undergoing abrupt changes in organization in a temporally- and spatially-regulated manner. It is not known how assemblies with the proper arrangement of septin subunits are built in the cell, or how they are reorganized during cycles of proliferation and development. The budding yeast septins represent an elegant and powerful system with which to identify cellular mechanisms regulating the organization of these multi-subunit macromolecular assemblies.
We are currently focused on several projects:
1) In collaboration with the lab of Prof. Eva Nogales at the Univ. of California, Berkeley, elucidate at nanometer resolution the organization of septin subunits within higher-order assemblies in Saccharomyces cerevisiae.
2) Determine how the early events of folding, nucleotide binding/hydrolysis, and oligomerization contribute to higher-order septin assembly.
3) Identify the mechanisms by which pre-existing septin assemblies are remodeled during developmental transitions (e.g., sporulation).
4) Search for examples of "structural inheritance", in which the proper conformation or organization of a newly-made protein-based assembly depends upon the presence of pre-existing copies of the same structure.
Weems AD, Johnson CR, Argueso JL, McMurray MA. Higher-order septin assembly is driven by GTP-promoted conformational changes: evidence from unbiased mutational analysis in Saccharomyces cerevisiae. Genetics doi: 10.1534/genetics.114.161182 (2014)
de Val N, McMurray MA, Lam LH, Hsiung CC, Bertin A, Nogales E, Thorner J. Native cysteine residues are dispensable for the structure and function of all five yeast mitotic septins. Proteins 81:1964-79 (2013)
Bertin A, McMurray MA, Thorner J, Peters P, Zehr E, McDonald KL, Thai L, Pierson J, Nogales E. Three-dimensional ultrastructure of the septin filament network in Saccharomyces cerevisiae. Molecular Biology of the Cell 23:423-32 (2012)
Garcia G III, Bertin A, Li Z, Song Y, McMurray MA, Thorner J, Nogales E. Subunit-dependent modulation of septin assembly: Budding yeast septin Shs1 promotes ring and gauze formation. Journal of Cell Biology 195:993-1004 (2011)
McMurray MA, Stefan CJ, Wemmer M, Odorizzi G, Emr SD, Thorner J. Genetic interactions with mutations affecting septin assembly reveal ESCRT functions in budding yeast cytokinesis. Biological Chemistry 392:699 (2011).
McMurray MA, Bertin A, Garcia III G, Lam L, Nogales EE and Thorner J. Septin filament formation is essential in budding yeast. Developmental Cell 20:540-9 (2011)
Bertin A, McMurray MA, Thai L, Garcia III G, Votin V, Grob P, Allyn T, Thorner J and Nogales EE. Phosphatidylinositol-4,5-bisphosphate promotes budding yeast septin filament assembly and organization. Journal of Molecular Biology 404:711 (2010)
Garrenton LS, Stefan C, McMurray MA, Emr SD and Thorner J. Pheromone-induced anisotropy in yeast plasma membrane phosphatidylinositol-4,5-bisphosphate distribution is required for MAPK signaling. Proceedings of the National Academy of Sciences of the United States of America 107:11805 (2010)
McMurray MA and Thorner J. Septins: molecular partitioning and the generation of cellular asymmetry. Cell Division 4:18. (2009)
McMurray MA and Thorner J. Reuse, replace, recycle: Specificity in subunit inheritance and assembly of higher-order septin structures during mitotic and meiotic division in budding yeast. Cell Cycle 8(2):195-203. (2009)
McMurray MA and Thorner J. Biochemical properties and supramolecular architecture of septin hetero-oligomers and septin filaments. In: Hall PA, Russell SEG, Pringle JR, eds. The Septins. Chicester, West Sussex, UK: John Wiley & Sons, Ltd., pp. 49-100. (2008)
McMurray MA, Thorner J. Septin stability and recycling during dynamic structural transitions in cell division and development. Current Biology 18:1203 (2008)
Bertin A*, McMurray MA*, Grob P*, Park SS, Garcia G 3rd, Patanwala I, Ng HL, Alber T, Thorner J, Nogales E. Saccharomyces cerevisiae septins: supramolecular organization of heterooligomers and the mechanism of filament assembly. Proceedings of the National Academy of Sciences of the United States of America 105:8274 (2008) * these authors contributed equally to this work.
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