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Instruments / Technical Area	Publication Details	Published	Actions
I02-Macromolecular Crystallography I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	A topological switch in CFTR modulates channel activity and sensitivity to unfolding Daniel Scholl , Maud Sigoillot , Marie Overtus , Rafael Colomer Martinez , Chloé Martens , Yiting Wang , Els Pardon , Toon Laeremans , Abel Garcia-Pino , Jan Steyaert , David N. Sheppard , Jelle Hendrix , Cedric Govaerts Nature Chemical Biology 245 DOI: 10.1038/s41589-021-00844-0 Diamond Proposal Number(s): [12718, 9426] Show Abstract ▼ Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is essential to maintain fluid homeostasis in key organs. Functional impairment of CFTR due to mutations in the cftr gene leads to cystic fibrosis. Here, we show that the first nucleotide-binding domain (NBD1) of CFTR can spontaneously adopt an alternate conformation that departs from the canonical NBD fold previously observed. Crystallography reveals that this conformation involves a topological reorganization of NBD1. Single-molecule fluorescence resonance energy transfer microscopy shows that the equilibrium between the conformations is regulated by adenosine triphosphate binding. However, under destabilizing conditions, such as the disease-causing mutation F508del, this conformational flexibility enables unfolding of the β-subdomain. Our data indicate that, in wild-type CFTR, this conformational transition of NBD1 regulates channel function, but, in the presence of the F508del mutation, it allows domain misfolding and subsequent protein degradation. Our work provides a framework to design conformation-specific therapeutics to prevent noxious transitions.	Aug 2021
I24-Microfocus Macromolecular Crystallography	Phosphorylation decelerates conformational dynamics in bacterial translation elongation factors Ariel Talavera , Jelle Hendrix , Wim Versees , Dukas Jurėnas , Katleen Van Nerom , Niels Vandenberk , Ranjan Kumar Singh , Albert Konijnenberg , Steven De Gieter , Daniel Castro-Roa , Anders Barth , Henri De Greve , Frank Sobott , Johan Hofkens , Nikolay Zenkin , Remy Loris , Abel Garcia-Pino Science Advances 4 DOI: 10.1126/sciadv.aap9714 Diamond Proposal Number(s): [17150] Open Access Show Abstract ▼ Abstract: Bacterial protein synthesis is intricately connected to metabolic rate. One of the ways in which bacteria respond to environmental stress is through posttranslational modifications of translation factors. Translation elongation factor Tu (EF-Tu) is methylated and phosphorylated in response to nutrient starvation upon entering stationary phase, and its phosphorylation is a crucial step in the pathway toward sporulation. We analyze how phosphorylation leads to inactivation of Escherichia coli EF-Tu. We provide structural and biophysical evidence that phosphorylation of EF-Tu at T382 acts as an efficient switch that turns off protein synthesis by decoupling nucleotide binding from the EF-Tu conformational cycle. Direct modifications of the EF-Tu switch I region or modifications in other regions stabilizing the β-hairpin state of switch I result in an effective allosteric trap that restricts the normal dynamics of EF-Tu and enables the evasion of the control exerted by nucleotides on G proteins. These results highlight stabilization of a phosphorylation-induced conformational trap as an essential mechanism for phosphoregulation of bacterial translation and metabolism. We propose that this mechanism may lead to the multisite phosphorylation state observed during dormancy and stationary phase.	Mar 2018

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