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Instruments / Technical Area	Publication Details	Published	Actions
B23-Circular Dichroism	Allosteric inhibition of human exonuclease1 (hExo1) through a novel extended β-sheet conformation Aminu Argungu Umar , Susan Liddell , Rohanah Hussain , Giuliano Siligardi , Gemma Harris , Stephen Carr , Karishma Asiani , Darren M. Gowers , Mark Odell , David J. Scott Biochimica Et Biophysica Acta (bba) - General Subjects 1864 DOI: 10.1016/j.bbagen.2020.129730 Diamond Proposal Number(s): [15313, 14658, 14430] Show Abstract ▼ Abstract: Background: Human Exonuclease1 (hExo1) participates in the resection of DNA double-strand breaks by generating long 3′-single-stranded DNA overhangs, critical for homology-based DNA repair and activation of the ATR-dependent checkpoint. The C-terminal region is essential for modulating the activity of hExo1, containing numerous sites of post-translational modification and binding sites for partner proteins. Methods: Analytical Ultracentrifugation (AUC), Dynamic Light Scattering (DLS), Circular Dichroism (CD) spectroscopy and enzymatic assays. Results: AUC and DLS indicates the C-terminal region has a highly extended structure while CD suggest a tendency to adopt a novel left-handed β-sheet structure, together implying the C-terminus may exhibit a transient fluctuating structure that could play a role in binding partner proteins known to regulate the activity of hExo1. Interaction with 14–3-3 protein has a cooperative inhibitory effect upon DNA resection activity, which indicates an allosteric transition occurs upon binding partner proteins. Conclusions: This study has uncovered that hExo1 consist of a folded N-terminal nuclease domain and a highly extended C-terminal region which is known to interact with partner proteins that regulates the activity of hExo1. A positively cooperative mechanism of binding allows for stringent control of hExo1 activity. Such a transition would coordinate the control of hExo1 by hExo1 regulators and hence allow careful coordination of the process of DNA end resection.	Dec 2020
I02-Macromolecular Crystallography I03-Macromolecular Crystallography	Structure of Cu(I)-Bound DJ-1 Reveals a Biscysteinate Metal Binding Site at the Homodimer Interface: Insights into Mutational Inactivation of DJ-1 in Parkinsonism Marc Puno , Nisha A. Patel , Simon Geir Møller , Carol V. Robinson , Peter Moody , Mark Odell Journal Of The American Chemical Society 135 (43), 15974 - 15977 DOI: 10.1021/ja406010m PMID: 24144264 Diamond Proposal Number(s): [6388] Show Abstract ▼ Abstract: The Parkinsonism-associated protein DJ-1 has been suggested to activate the Cu–Zn superoxide dismutase (SOD1) by providing its copper cofactor. The structural and chemical means by which DJ-1 could support this function is unknown. In this study, we characterize the molecular interaction of DJ-1 with Cu(I). Mass spectrometric analysis indicates binding of one Cu(I) ion per DJ-1 homodimer. The crystal structure of DJ-1 bound to Cu(I) confirms metal coordination through a docking accessible biscysteinate site formed by juxtaposed cysteine residues at the homodimer interface. Spectroscopy in crystallo validates the identity and oxidation state of the bound metal. The measured subfemtomolar dissociation constant (Kd = 6.41 × 10–16 M) of DJ-1 for Cu(I) supports the physiological retention of the metal ion. Our results highlight the requirement of a stable homodimer for copper binding by DJ-1. Parkinsonism-linked mutations that weaken homodimer interactions will compromise this capability.	Oct 2013

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