CHESS DMR At last: Insights into membrane fusion and disease Joel Brock, Cornell University, DMR Model for atlastin-mediated membrane fusion. Phosphate release, relaxation and subsequent disassembly of the dimer lead to membrane curvature and stress, allowing fusion to occur spontaneously. Intellectual Merit: The protein called atlastin-1 is involved in both the synthesis of important cellular molecules and their transport to the appropriate parts of the cell. Using X-ray crystallography (CHESS, beamline A1), researchers in the Sondermann group have uncovered new insights into the function of atlastin-1. They solved the structure of atlastin-1 when it is bound to small molecules that mimic GTP. Two atlastin molecules dimerized in a tight interaction to bring opposing membranes into close proximity. They also used Förster Resonance Energy Transfer (FRET) to monitor the timing and nature of events when atlastin-1 binds to and hydrolyzes GTP. This work revealed how two parts of the protein work together to enable it to bind GTP and dimerize, and revealing a novel method of regulation for this type of protein. With this new information, researchers will be able to study mutations causing Hereditary Spastic Paraplegia (HSP) and Hereditary Sensory Neuropathy (HSN) diseases in a more directed fashion, and possibly identify which part of the mechanism each mutation affects. L. J Byrnes, A. Singh, K. Szeto, N. M Benvin, J. P O’Donnell, W. R Zipfel and H. Sondermann, “Structural basis for conformational switching and GTP loading of the large G protein atlastin,” The EMBO Journal (2013) 32, 369–384.

CHESS DMR L. J Byrnes, A. Singh, K. Szeto, N. M Benvin, J. P O’Donnell, W. R Zipfel and H. Sondermann, “Structural basis for conformational switching and GTP loading of the large G protein atlastin,” The EMBO Journal (2013) 32, 369–384. Broader Impacts: Within every cell of the human body lies an intricate network of membrane tubules and sheets tasked with orchestrating the processing of molecules necessary to keep cells alive. This network, called the endoplasmic reticulum (ER), is involved in both the synthesis of molecules and their transport to the appropriate parts of the cell. The ER employs many different types of proteins to accomplish this task. One subset of these proteins keeps the complex structure of the ER intact so that it can continue to perform its necessary function. When this structure breaks down, it can result in diseases. Researchers using x-ray crystallography at the CHESS A1 station uncovered a novel method of regulation for this type of protein system, opening new avenues to study mutations causing Hereditary Spastic Paraplegia (HSP) and Hereditary Sensory Neuropathy (HSN) diseases in a more directed fashion, and possibly identify which part of the mechanism each mutation affects. (A) Topology of atlastin-1. This N-terminal, cytoplasmic unit interacts with the lipid membrane. (B) Protomer structures of crystal forms 1 and 2. At last: Insights into membrane fusion and disease Joel Brock, Cornell University, DMR

CHESS DMR (a) A partial Au–Cu–Si composition diagram with critical cooling rates for complete vitrification. (b) 40 keV X-rays cause diffraction in transmission. (c) A diffraction pattern (black) indicating crystalline and amorphous phases. J. M. Gregoire, P. J. McCluskey, D. Dale, S. Ding, J. Schroers and J. J. Vlassak, "Combining combinatorial nanocalorimetry and X-ray diffraction techniques to study the effects of composition and quench rate on Au– Cu–Si metallic glasses," Scripta Materialia, vol. 66, pp , Intellectual Merit: Glassy materials can be mysterious – on cooling over a narrow range of temperature, the melt solidifies but retains atomic structure similar to that of the high temperature liquid. The majority of ternary glassy systems require very high cooling rates to form, and are difficult to study with traditional calorimetry. Vlassak and his team studied gold-based metallic glasses, which are of particular interest due the distinctive properties of Au-rich alloys, such as high corrosion resistance and superior electrical properties. The Vlassak group developed a thin-film nanocalorimeter, which allows the study of fundamental properties of metallic glasses at ultrafast heating and cooling rates. In-situ X-ray diffraction can determined the amount of material in glassy or crystalline phases but an intense monochromatic x-ray source (the CHESS A2 end station) was required to study the vanishingly small quantities of material in the nanocalorimeter devices. Using CHESS, they were able to map the critical cooling rate for vitrification over an array of 22 compositions in the Au–Cu–Si system and characterize the phase changes at unprecedented heating rates for metallic glass systems. A New Approach to the Glass Transition Joel Brock, Cornell University, DMR

CHESS DMR Composition trends over 22-samples. (a) Si:Cu ratio for the glass- forming component; (b) glass transition temperature (average temperature of endothermic reaction) after approximately 2x10 4 K/s quench; (c) the total enthalpy of this glass reaction, normalized by the molar fraction of the amorphous phase. J. M. Gregoire, P. J. McCluskey, D. Dale, S. Ding, J. Schroers and J. J. Vlassak, "Combining combinatorial nanocalorimetry and X-ray diffraction techniques to study the effects of composition and quench rate on Au–Cu–Si metallic glasses," Scripta Materialia, vol. 66, pp , Broader Impacts: Glass is everywhere, so it might come as a surprise that it is poorly understood. Glass is different – on cooling over a narrow range of temperature, known as the glass transition, the liquid solidifies but retains an atomic structure that is very similar to that of the liquid melt. In fact, the 125th anniversary issue of Science magazine identified the nature of the glass transition as one of the great outstanding mysteries driving basic scientific research. Recently a group of researchers from Harvard University, led by Professor Joost Vlassak, and the Cornell High Energy Synchrotron Source have combined efforts to develop new experimental capabilities with the potential to provide new insights into the nature of the glass transition. They conclude that these new experimental capabilities “offer unique opportunities to explore the asymmetry of crystallization kinetics upon heating and cooling, to directly correlate the effect of cooling rate on the glass transition and crystallization upon heating, and to narrow the vast gap between conditions in simulations and typical experiments.” A New Approach to the Glass Transition Joel Brock, Cornell University, DMR