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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography	The structural basis for Z α1-antitrypsin polymerization in the liver Sarah V. Faull , Emma L. K. Elliston , Bibek Gooptu , Alistair M. Jagger , Ibrahim Aldobiyan , Adam Redzej , Magd Badaoui , Nina Heyer-Chauhan , S. Tamir Rashid , Gary M. Reynolds , David H. Adams , Elena Miranda , Elena V. Orlova , James A. Irving , David A. Lomas Science Advances 6 DOI: 10.1126/sciadv.abc1370 Diamond Proposal Number(s): [17201] Open Access Show Abstract ▼ Abstract: The serpinopathies are among a diverse set of conformational diseases that involve the aberrant self-association of proteins into ordered aggregates. α1-Antitrypsin deficiency is the archetypal serpinopathy and results from the formation and deposition of mutant forms of α1-antitrypsin as “polymer” chains in liver tissue. No detailed structural analysis has been performed of this material. Moreover, there is little information on the relevance of well-studied artificially induced polymers to these disease-associated molecules. We have isolated polymers from the liver tissue of Z α1-antitrypsin homozygotes (E342K) who have undergone transplantation, labeled them using a Fab fragment, and performed single-particle analysis of negative-stain electron micrographs. The data show structural equivalence between heat-induced and ex vivo polymers and that the intersubunit linkage is best explained by a carboxyl-terminal domain swap between molecules of α1-antitrypsin.	Oct 2020
Krios I-Titan Krios I at Diamond	Structural basis of Cullin 2 RING E3 ligase regulation by the COP9 signalosome Sarah V. Faull , Andy M. C. Lau , Chloe Martens , Zainab Ahdash , Kjetil Hansen , Hugo Yebenes , Carla Schmidt , Fabienne Beuron , Nora B. Cronin , Edward Morris , Argyris Politis Nature Communications 10 DOI: 10.1038/s41467-019-11772-y Diamond Proposal Number(s): [15621, 16023] Open Access Show Abstract ▼ Abstract: Cullin-Ring E3 Ligases (CRLs) regulate a multitude of cellular pathways through specific substrate receptors. The COP9 signalosome (CSN) deactivates CRLs by removing NEDD8 from activated Cullins. Here we present structures of the neddylated and deneddylated CSN-CRL2 complexes by combining single-particle cryo-electron microscopy (cryo-EM) with chemical cross-linking mass spectrometry (XL-MS). These structures suggest a conserved mechanism of CSN activation, consisting of conformational clamping of the CRL2 substrate by CSN2/CSN4, release of the catalytic CSN5/CSN6 heterodimer and finally activation of the CSN5 deneddylation machinery. Using hydrogen-deuterium exchange (HDX)-MS we show that CRL2 activates CSN5/CSN6 in a neddylation-independent manner. The presence of NEDD8 is required to activate the CSN5 active site. Overall, by synergising cryo-EM with MS, we identify sensory regions of the CSN that mediate its stepwise activation and provide a framework for understanding the regulatory mechanism of other Cullin family members.	Sep 2019

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