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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography	RING domains act as both substrate and enzyme in a catalytic arrangement to drive self-anchored ubiquitination Leo Kiss , Dean Clift , Nadine Renner , David Neuhaus , Leo C. James Nature Communications 12 DOI: 10.1038/s41467-021-21443-6 Diamond Proposal Number(s): [15916, 21426] Open Access Show Abstract ▼ Abstract: Attachment of ubiquitin (Ub) to proteins is one of the most abundant and versatile of all posttranslational modifications and affects outcomes in essentially all physiological processes. RING E3 ligases target E2 Ub-conjugating enzymes to the substrate, resulting in its ubiquitination. However, the mechanism by which a ubiquitin chain is formed on the substrate remains elusive. Here we demonstrate how substrate binding can induce a specific RING topology that enables self-ubiquitination. By analyzing a catalytically trapped structure showing the initiation of TRIM21 RING-anchored ubiquitin chain elongation, and in combination with a kinetic study, we illuminate the chemical mechanism of ubiquitin conjugation. Moreover, biochemical and cellular experiments show that the topology found in the structure can be induced by substrate binding. Our results provide insights into ubiquitin chain formation on a structural, biochemical and cellular level with broad implications for targeted protein degradation.	Feb 2021
I24-Microfocus Macromolecular Crystallography	A lysine ring in HIV capsid pores coordinates IP6 to drive mature capsid assembly Nadine Renner , Donna L. Mallery , K. M. Rifat Faysal , Wang Peng , David Jacques , Till Böcking , Leo C. James Plos Pathogens 17 DOI: 10.1371/journal.ppat.1009164 Diamond Proposal Number(s): [15916, 21426] Open Access Show Abstract ▼ Abstract: The HIV capsid self-assembles a protective conical shell that simultaneously prevents host sensing whilst permitting the import of nucleotides to drive DNA synthesis. This is accomplished through the construction of dynamic, highly charged pores at the centre of each capsid multimer. The clustering of charges required for dNTP import is strongly destabilising and it is proposed that HIV uses the metabolite IP6 to coordinate the pore during assembly. Here we have investigated the role of inositol phosphates in coordinating a ring of positively charged lysine residues (K25) that forms at the base of the capsid pore. We show that whilst IP5, which can functionally replace IP6, engages an arginine ring (R18) at the top of the pore, the lysine ring simultaneously binds a second IP5 molecule. Dose dependent removal of K25 from the pore severely inhibits HIV infection and concomitantly prevents DNA synthesis. Cryo-tomography reveals that K25A virions have a severe assembly defect that inhibits the formation of mature capsid cones. Monitoring both the kinetics and morphology of capsids assembled in vitro reveals that while mutation K25A can still form tubes, the ability of IP6 to drive assembly of capsid cones has been lost. Finally, in single molecule TIRF microscopy experiments, capsid lattices in permeabilised K25 mutant virions are rapidly lost and cannot be stabilised by IP6. These results suggest that the coordination of IP6 by a second charged ring in mature hexamers drives the assembly of conical capsids capable of reverse transcription and infection.	Feb 2021

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