Grant J. Jensen
California Institute of Technology
1200 E. California Blvd.
Pasadena, CA 91125
2004 Searle Scholar
In scienceDs approach towards a comprehensive understanding of cell biology, sequencing programs are delivering complete lists of genes; proteomic efforts are cataloguing the functions, relative expression levels, and actual amounts of each protein present in cells at various times; comprehensive tagging studies are fluorescently labeling every protein in several cell types and roughly locating them at different stages of the cell cycle; and structural genomics initiatives are automating the tools required to solve the structure of every protein domain found in nature. Yet if we were to combine all this information in an attempted cell simulation, we would find one critical piece missing: the ultrastructure of the cell at the molecular level. Stated simply, cells are not merely Ubags^ of enzymes. Rather, Uthe entire cell can be viewed as a factory that contains an elaborate network of interlocking assembly lines, each of which is composed of a set of large protein machines^ (B. Alberts, Cell 92:291-294). Unfortunately, the structural details of those networks of machines are yet to be discovered for lack of an effective tool. I believe cryoelectron microscopy (cryoEM) will become that tool, and my present interests are in both advancing the technique and applying it to important biological problems where it is most needed.
Another major project is comprehensive structural analysis of a "minimal" cell, namely Mycoplasma genitalium (MG). There is good reason to believe that state-of-the-art microscopes will deliver "molecular resolution" tomograms of these small bacteria, such that large protein complexes will be visible within their native cellular context. I expect that within the next decade, all the information needed to simulate this most simple of all free-living organisms will be obtained. My lab will contribute the essential medium resolution (~20_) structural information: the spatial organization of the cell, the identification and location of large complexes, the nature of the cytoskeleton, the characterization of diffusion constraints, etc., or in other words all the ways in which the cell is not just a "bag" of freely diffusing small enzymes and substrates. This may include purifying protein complexes from MG and determining their structures by single particle analysis, as well as recording tomograms of whole cells. Ultimately we will fit together the entire cellular puzzle using atomic models of individual domains, near-atomic resolution single particle reconstructions of complexes, and medium resolution tomograms of entire cells. MG is ideal because it is simultaneously (1) the smallest free-living organism known, which will improve our imaging; (2) the simplest free-living organism, having only ~500 genes; and (3) the organism which will soon have the most comprehensively characterized proteome, since it is the target of the Berkeley high-throughput structural genomics consortium dedicated to solve the structure of each of its proteins.
In a similar study targeting a more complex but more intensely studied bacteria that localizes many of its proteins and nucleic acids internally, we are recording tomograms of Caulobacter crescentus.
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