Probing the Effects of Local Frustration in the Folding of a Multidomain Protein |
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| Institution: | 1. Department of Biochemistry and Molecular Biophysics, Box 8231, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States;2. Department of Physics, Washington University in St. Louis, St. Louis, MO 63130, United States;1. Department of Pharmaceutical and Biological Chemistry, School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK;2. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia;3. ARC Centre for Fragment-Based Design, Monash University, Parkville, Victoria 3052, Australia;1. New York Structural Biology Center, New York, NY, USA;2. Department of Biomedical Sciences, University at Albany, Albany, NY, USA;3. Division of Infectious Diseases, Wadsworth Center, New York State Department of Health, Albany, NY, USA;4. Department of Molecular Cell Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, Oslo, Norway;5. Department of Biosciences, University of Oslo, Oslo, Norway;1. Department of Molecular Biophysics, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Str. 10, 13125 Berlin, Germany;2. Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Huangshan Road 443, Hefei 230027, China;3. Structural Chemistry and Computational Biophysics Group, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Str. 10, 13125 Berlin, Germany;4. Institut für Biologie, Humboldt-Universität zu Berlin, Invalidenstraße 42, 10115 Berlin, Germany;1. Center on Membrane Protein Production and Analysis (COMPPÅ), New York Structural Biology Center (NYSBC), New York, NY 10027, USA;2. Rockefeller University, New York, NY 10065, USA;3. Schrödinger, Inc., New York, NY 10036, USA;4. Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA;5. Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA |
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| Abstract: | Our current knowledge of protein folding is primarily based on experimental data obtained from isolated domains. In fact, because of their complexity, multidomain proteins have been elusive to the experimental characterization. Thus, the folding of a domain in isolation is generally assumed to resemble what should be observed for more complex structural architectures. Here we compared the folding mechanism of a protein domain in isolation and in the context of its supramodular multidomain structure. By carrying out an extensive mutational analysis we illustrate that while the early events of folding are malleable and influenced by the absence/presence of the neighboring structures, the late events appear to be more robust. These effects may be explained by analyzing the local frustration patterns of the domain, providing critical support for the funneled energy landscape theory of protein folding, and highlighting the role of protein frustration in sculpting the early events of the reaction. |
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| Keywords: | PDZ ϕ-value analysis energy landscape tandem intermediate |
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