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ItemStructural Basis for Iron Piracy by Pathogenic Neisseria(Georgia Institute of Technology, 2012-10-16) Buchanan, SusanNeisseria are obligate human pathogens causing bacterial meningitis, septicemia, and gonorrhea. Neisseria require iron for survival and can extract it directly from human transferrin for transport across the outer membrane. The transport system consists of TbpA, an integral outer membrane protein, and TbpB, a co-receptor attached to the cell surface; both proteins are potentially important vaccine and therapeutic targets. Two key questions driving Neisseria research are: 1) how human transferrin is specifically targeted, and 2) how the bacteria liberate iron from transferrin at neutral pH. To address them, we solved crystal structures of the TbpA-transferrin complex and of the corresponding co-receptor TbpB. We characterized the TbpB-transferrin complex by small angle X-ray scattering and the TbpA-TbpB-transferrin complex by electron microscopy. Collectively, our studies provide a rational basis for the specificity of TbpA for human transferrin, show how TbpA promotes iron release from transferrin, and elucidate how TbpB facilitates this process.
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ItemDevelopment and Evolution of Vertebrate Development and Evolution of Vertebrate(Georgia Institute of Technology, 2012-04-24) Tabin, CliffordDr. Tabin's laboratory studies the genetic basis by which form and structure are regulated during vertebrate development. They combine classical methods of experimental embryology with modern molecular and genetic techniques for regulating gene expression during embryogenesis.
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ItemThe ESCRT pathway in HIV Budding and Cell Division(Georgia Institute of Technology, 2012-01-31) Sundquist, WesleyThe Endosomal Sorting Complexes Required for Transport (ESCRT) pathway mediates intraluminal endosomal vesicle formation, budding of HIV-1 and other enveloped viruses, and the final abscission step of cytokinesis in mammals and archaea. I will review our current understanding of the roles of different EXCRT factors in HIV budding, and then discuss our recent findings that in addition to their roles in abscission, EXCRT factors are also required for several key steps in mitosis, including creation of the bipolar spindle and proper pairing and segregation of sister chromatids. Our studies indicate that the EXCRT pathway functions at both centrosomes and centromeres during mitosis, and then at midbodies during abscission, thereby helping to ensure ordered progression through the different stages of cell division.
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ItemNew approaches to studying the growth and size regulation of mammalian cells(Georgia Institute of Technology, 2012-01-24) Kirschner, MarcThe study of cell growth has been limited primarily by the lack of accurate enough means of measuring the growth of cells as they traverse the cell cycle. There are several theoretical models of growth that have been impossible to evaluate because the methods for measuring growth have been too inaccurate to distinguish among them. In particular, if cells grow proportional to their mass, which of course doubles each cell cycle, then it is likely that the variation in cell size in a population would increase without limit. This is simply because cell division is rarely completely symmetric, producing smaller cells that would grow slower and larger cells that would grow faster. On the other hand, if cells added equal mass per unit time this undesirable outcome could be avoided. There are ideas that size control may not exist but simply be driven by exogenous and independent controls of cell cycle and growth, size being simply a resultant of these explicity controls. Yet the very strict size regulation of different cell types, suggests that cell size is an evolutionary optimum for different functions and hence, cells should have a homeostatic mechanism for maintaining cell size. There are other speculations that cells grow to a defined size and then divide, making cell division a slave to cell growth. The opposite is also possible that passage through the cell cycle feeds back on cell growth. To approach these questions we have developed two new analytical techniques of exquisite sensitivity. In collaboration with Scott Manalis at MIT, we used his suspended microchannel resonator to measure cell mass to 0.01% and to do that for as many as 8 generations without causing any known harm to the cells. This technique pointed to a sharp transition of growth at the G1/S transition. It also shows that a size threshold does not exist in a mammalian cell line but instead there is convergence of cell growth rates at G1/S. Another technique which Ran Kafri, a postdoc in my lab and Galit Lahav's lab developed used a static population based approach to derive very sensitive kinetic features based on the ergodic assumption of steady state growth. This method opens up many new measurements not possible in growing individual cells; here temporal resolution and sensitivity is increased markedly as cell numbers exceed a million. This method also described a period at the feedback on growth rate at the G1/S transition. These new measurements suggest that there is a sizing mechanism in mammalian cells that reduces variation in the cell cycle by affecting growth rate and size dependence of growth rate. Such a mechanism is liked to be tuned and respond differently in different cell types and under different conditions.
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ItemNew Biology from Natural Metamorphosis of a Conventional Class of Enzymes(Georgia Institute of Technology, 2011-11-15) Schimmel, PaulA group of enzymes known as aminoacyl tRNA synthetases interpret genetic information through catalysis of aminoacylation reactions that establish the genetic code. Errors of interpretation are corrected by a universal mechanism that is facilitated by novel domains incorporated into these same enzymes. This error-correcting activity is closely associated with the beginnings of living organism, and defects in this activity lead to disease and even lethality. The paradigm of incorporating novel domain additions to develop a specialized activity has been expanded in higher organisms where these domain additions are incorporated into a large library of naturally occurring new structures arising from alternative splicing and proteolysis. This metamorphosis into new structures gives rise to a diversity of new functions that go beyond translation of genetic information. Investigations of several of these structural metamorphs have uncovered new biology that has clinical applications.
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ItemProtein Folding Inside Cells and Other Crowded Environments(Georgia Institute of Technology, 2011-11-08) Gruebele, MartinComputer simulations are reaching the point where folding of small proteins in vitro can be successfully achieved ‘ab initio’ by molecular dynamics. Experiments can help further calibrate simulations, and I will discuss two examples. Experiments can also move forward to study protein dynamics in complex environment, such as the interior of the cell. There, modulation of the energy landscape and local viscosity can affect protein stability and folding kinetics. I will discuss experimental examples. The ultimate question, which cannot be answered yet, is whether cells evolved to gainfully modulate protein landscapes after post translational folding and modification, or whether microenvironments in the cell just provide stochastic modulation.
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ItemCheminformatic and assay-performance profiling of small-molecule screening collections(Georgia Institute of Technology, 2011-05-17) Clemons, Paul A .Quantitative decisions about properties and behavior of compound sets are important in building screening collections for smallmolecule probes and drugs. Decisions about individual compounds typically dominate such discussions: individual compounds pass or fail filtering rules, individual compounds hit or not in assays, etc. In this presentation, we focus on analyses directed at sets of compounds rather than individual members. We start with bioinformatic analysis of natural product and drug targets that motivates the need for new sources of synthetic small molecules. Next, we use sets of molecules from 3 sources (commercial, natural, academic) to show that different computed chemical properties (cheminformatic profiles) provide different chemical intuition about diversity of compound sets, and how quantifying these relationships can provide guidance to synthetic chemists. In the second part, we show that arrays of biological performance measurements (assay-performance profiles) can be used, instead of chemical structure, as a basis for small-molecule similarity, with implications for target identification and lead hopping. To illustrate connections between computed and measured properties, we describe a structured small-molecule profiling experiment in which 15,000 compounds were exposed to 100 different protein-binding assays. We show how different computed molecular complexity and shape descriptors accord with specificity of performance in protein-binding assays. Finally, using the same dataset, we introduce a measure of assay-performance diversity based on information entropy, and show how it might be used to judge relationships between computed properties and performance diversity of compound collections.
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ItemHow do proteins do all of that as seen by hydrogen exchange. Protein folding, GroEL function, lipoprotein structure(Georgia Institute of Technology, 2011-05-10) Englander, S. WalterThe talk will illustrate the use of hydrogen exchange methods to learn about biophysical properties and functional behaviors of protein molecules. Hydrogen exchange has been measured by older tritium exchange techniques, by 2D NMR, and most recently by mass spectrometry. Examples of applications will illustrate how each method provides specific advantages for different applications. Topics to be considered include how proteins fold, and how GroEL helps proteins to fold. Also recent progress in extending hydrogen exchange to the study of large and even insoluble protein systems using mass spectrometry will be shown.
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ItemDismantling Complex Problems into their Simple Substrates: From Embryonic Stems Cells to Global Peace(Georgia Institute of Technology, 2011-03-09) Zucker, Howard A.In the constantly changing world that we all live in today, problems appear to surface that have many faces depending upon one’s vantage point. At times it may be possible to distill some of the complexities into smaller subunits that are easier to tackle. Today’s lecture will look at several examples and personal experiences with these dilemmas. Included in the presentation is a discussion on how a child’s toy can help improve health for millions of illiterate people, why a device in the hands of billions can guarantee safety of the pharmaceutical supply chain, the way a few simple questions can determine whether billions spent on peace are actually making a difference and the applicability of an accepted medical practice to expanding the use of stem cells. In addition, a discussion on how historical examples can be used to help develop national vaccination programs and can lay a foundation for tissue engineering research, as well as how research into one biological system can possibly solve many medical problems, and at the same time help contribute to alternative energy sources
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ItemEvolution: from atoms to organisms(Georgia Institute of Technology, 2011-02-15) Shakhnovich, EugeneModern Biology is deeply rooted in Darwinian principles of mutations and selection. Population Genetics aims to address the effects of mutations and selection on populations in a quantitative way within the basic paradigm of ‘’fitness landscape’’, which postulates how genotypicchanges affect phenotype (e.g., fitness or growth rate of an organism or a tissue). No clear connection between the fitness effects of mutations and their effect on molecular properties of proteins has been systematically established – proteins are still treated as ‘’black boxes’’ in most population and organism level studies of evolution. In this talk I will present a systematic theoretical and experimental effort in our lab to go beyond this paradigm by developing multiscale models which relate molecular properties of proteins (their folding, function and interactions) to fitness of carrier organisms. By analyzing such models (both in simulations and analytically) we derived distribution of proteins stabilities which is very close to experimentally observed ones and predict its dependence of mutation rates and population size, linking ecology and molecular biophysics. Further we predicted and found correlation between protein stabilities and their abundances in cells as well as between protein abundances and strength of their interactions with other proteins. We discovered a universal physics-based speed limit on mutation rates in all organisms – ~6 missense mutations per essential part of the genome per replication. Further, we systematically experimentally probe fitness landscape by making controllable biophysical changes in proteins (varying stability and folding rates by mutations and abundances by manipulating upstream regions) with subsequent incorporation of mutant genes into E.coli chromosome and evaluating fitness of mutant strains in competition with wild-type. Our experiments confirm basic features of physics-based fitness landscape and add important new insights on how to make them more comprehensive and accurate.