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TSRI Scientific Report 2005



Cover Artwork


On the front cover: Adjacent cells communicate with each other through gap junction membrane channels, which allow passage of ions and small molecules that coordinate metabolic and electrical activities within tissues. Gap junction channels connect the cytoplasms of adjacent cells by means of an intercellular conduit formed by the end-to-end docking of 2 hemichannels, each composed of 6 connexin subunits. The left, middle, and right images are side, tilted, and top views, respectively. The protein channels have an outside diameter of about 65 Å, and the central pore narrows to about 15 Å. A Ca molecular model (yellow ribbons) for the 24 membrane-spanning a-helices of the hemichannels was derived by combining the information from a computational analysis of connexin sequences, the results of more than a decade of biochemical studies, and the constraints provided by a 3-dimensional map derived by using electron cryocrystallography (blue). Although individually, none of these approaches provided high-resolution information, their sum yielded an atomic model that can be used to predict how connexin mutations (red spheres) may interfere with formation of functional channels by disrupting helix-helix packing. Molecular graphics by Michael E. Pique and Mark Yeager, M.D., Ph.D., Department of Cell Biology. For details, see the report from the laboratory of Dr. Yeager.


Inside front cover: Fibroblasts were dissociated from transgenic mice expressing a fusion of the endogenous clock gene PER2 with a luciferase reporter and were imaged continuously for more than 8 days by using a low-noise CCD camera. Bioluminescence rhythms of 75 fibroblasts from a single experiment are represented in this plot. Each horizontal raster line represents a single cell, with elapsed time plotted left to right. Luminescence intensity data were normalized for amplitude and then were color coded: higher than average values are red, and lower than average values are green. The cells are sorted in order of deviation from average start phase, so that cells synchronized by a change in medium at the start of the experiment appear in the lower half of the plot. Work done in the laboratory of Steve A. Kay, Ph.D., Department of Cell Biology.


Inside back cover: Export of cargo (ball-and-stick icons) from the endoplasmic reticulum to the cell surface occurs through cargo-selective budding regions (lower electron microscopy image). Currently, cargo export is thought to be restricted to fully folded structures by “quality control” pathways. Surprisingly, analysis of protein-folding energetics and secretion in a collaboration between researchers in the laboratories of Bill Balch, Department of Cell Biology, and Jeff Kelly, Department of Chemistry, indicated that protein variants destabilized relative to the wild-type fold are secreted with wild-type efficiency, triggering deposition of aggregates of amyloid fibril in the extracellular space (upper image). Knowledge of the importance of the global energetics of the protein fold in secretion leads to a key shift in the understanding of the secretory pathway. Lower image kindly provided by G. Palade, M.D., University of California, San Diego, School of Medicine. Figure prepared by Mike E. Pique.


Back cover: Many viruses undergo large-scale structural changes at critical stages in their life cycles, including during assembly, maturation, infection of host cells, and genome expulsion. Solution x-ray scattering can be used to observe the changes directly and to determine how the complex virus machinery functions. Time-resolved solution x-ray scattering was used to monitor the maturation of the protective protein capsid of bacteriophage HK97. The results indicated that despite the structural complexity of this capsid (420 protein subunits arrayed in a T = 7 quasi-equivalent icosahedral lattice), the constituent subunits behave in a highly cooperative fashion, giving rise to an abrupt, 2-state transition from the initial prohead II state (yellow) to the expansion intermediate I state (blue). Work done by Kelly Lee, Ph.D., Research Associate in the laboratory of John E. Johnson, Ph.D., Department of Molecular Biology.