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Instruments / Technical Area	Publication Details	Published	Actions
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	The conserved C2 phospholipid‐binding domain in Delta contributes to robust Notch signalling Torcato Martins , Yao Meng , Boguslawa Korona , Richard Suckling , Steven Johnson , Penny A Handford , Susan M. Lea , Sarah J Bray Embo Reports 8 DOI: 10.15252/embr.202152729 Open Access Show Abstract ▼ Abstract: Accurate Notch signalling is critical for development and homeostasis. Fine-tuning of Notch–ligand interactions has substantial impact on signalling outputs. Recent structural studies have identified a conserved N-terminal C2 domain in human Notch ligands which confers phospholipid binding in vitro. Here, we show that Drosophila ligands Delta and Serrate adopt the same C2 domain structure with analogous variations in the loop regions, including the so-called β1-2 loop that is involved in phospholipid binding. Mutations in the β1-2 loop of the Delta C2 domain retain Notch binding but have impaired ability to interact with phospholipids in vitro. To investigate its role in vivo, we deleted five residues within the β1-2 loop of endogenous Delta. Strikingly, this change compromises ligand function. The modified Delta enhances phenotypes produced by Delta loss-of-function alleles and suppresses that of Notch alleles. As the modified protein is present on the cell surface in normal amounts, these results argue that C2 domain phospholipid binding is necessary for robust signalling in vivo fine-tuning the balance of trans and cis ligand–receptor interactions.	Aug 2021
I03-Macromolecular Crystallography	An inhibitor of complement C5 provides structural insights into activation Martin P. Reichhardt , Steven Johnson , Terence Tang , Thomas Morgan , Nchimunya Tebeka , Niko Popitsch , Justin C. Deme , Matthijs M. Jore , Susan Lea Proceedings Of The National Academy Of Sciences 117 DOI: 10.1073/pnas.1909973116 Diamond Proposal Number(s): [18069] Open Access Show Abstract ▼ Abstract: The complement system is a crucial part of innate immune defenses against invading pathogens. The blood-meal of the tick Rhipicephalus pulchellus lasts for days, and the tick must therefore rely on inhibitors to counter complement activation. We have identified a class of inhibitors from tick saliva, the CirpT family, and generated detailed structural data revealing their mechanism of action. We show direct binding of a CirpT to complement C5 and have determined the structure of the C5–CirpT complex by cryoelectron microscopy. This reveals an interaction with the peripheral macro globulin domain 4 (C5_MG4) of C5. To achieve higher resolution detail, the structure of the C5_MG4–CirpT complex was solved by X-ray crystallography (at 2.7 Å). We thus present the fold of the CirpT protein family, and provide detailed mechanistic insights into its inhibitory function. Analysis of the binding interface reveals a mechanism of C5 inhibition, and provides information to expand our biological understanding of the activation of C5, and thus the terminal complement pathway.	Dec 2019

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