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Instruments / Technical Area	Publication Details	Published
B21-High Throughput SAXS	The crystal structure of the EspB-EspK virulence factor-chaperone complex suggests an additional type VII secretion mechanism in M. tuberculosis Abril Gijsbers , Mathias Eymery , Ye Gao , Isabella Menart , Vanesa Vinciauskaite , Dritan Siliqi , Peter J. Peters , Andrew Mccarthy , Raimond B. G. Ravelli Journal Of Biological Chemistry 113 DOI: 10.1016/j.jbc.2022.102761 Diamond Proposal Number(s): [2357, 661] Open Access Show Abstract ▼ Abstract: Pathogenic species from the Mycobacterium genus are responsible for a number of adverse health conditions in humans and animals that threaten health security and the economy worldwide. Mycobacteria have up to five specialized secretion systems (ESX-1 to -5) that transport virulence factors across their complex cell envelope to facilitate manipulation of their environment. In pathogenic species, these virulence factors influence the immune system’s response and are responsible for membrane disruption and contributing to cell death. While structural details of these secretion systems have been recently described, gaps still remain in the structural understanding of the secretion mechanisms of most substrates. Here, we describe the crystal structure of M. tuberculosis ESX-1 secretion-associated substrate EspB bound to its chaperone EspK. We found that EspB interacts with the C-terminal domain of EspK through its helical tip. Furthermore, cryogenic electron microscopy, size exclusion chromatography analysis, and small angle X-ray scattering experiments show that EspK keeps EspB in its secretion-competent monomeric form and prevents its oligomerisation. The structure presented in this study suggests an additional secretion mechanism in ESX-1, analogous to the chaperoning of proline-glutamate (PE)–proline-proline-glutamate (PPE) proteins by EspG, where EspK facilitates the secretion of EspB in Mycobacterium species.	Dec 2022
B21-High Throughput SAXS	Structural analysis of the partially disordered protein EspK from Mycobacterium tuberculosis Abril Gijsbers , Nuria Sánchez-Puig , Ye Gao , Peter J. Peters , Raimond B. G. Ravelli , Dritan Siliqi Crystals 11 DOI: 10.3390/cryst11010018 Diamond Proposal Number(s): [21741, 21035] Open Access Show Abstract ▼ Abstract: For centuries, tuberculosis has been a worldwide burden for human health, and gaps in our understanding of its pathogenesis have hampered the development of new treatments. ESX-1 is a complex machinery responsible for the secretion of virulence factors that manipulate the host response. Despite the importance of these secreted proteins for pathogenicity, only a few of them have been structurally and functionally characterised. Here, we describe a structural study of the ESX-secretion associated protein K (EspK), a 74 kDa protein known to be essential for the secretion of other substrates and the cytolytic effects of ESX-1. Small-Angle X-ray Scattering (SAXS) data show that EspK is a long molecule with a maximal dimension of 228 Å. It consists of two independent folded regions at each end of the protein connected by a flexible unstructured region driving the protein to coexist as an ensemble of conformations. Limited proteolysis identified a 26 kDa globular domain at the C-terminus of the protein consisting of a mixture of α-helices and β-strands, as shown by circular dichroism (CD) and SAXS. In contrast, the N-terminal portion is mainly helical with an elongated shape. Sequence conservation suggests that this architecture is preserved amongst the different mycobacteria species, proposing specific roles for the N- and C-terminal domains assisted by the middle flexible linker.	Dec 2020
B21-High Throughput SAXS	Exploring the role of elongation Factor-Like 1 (EFL1) in Shwachman-Diamond syndrome through molecular dynamics Pietro Delre , Domenico Alberga , Abril Gijsbers , Nuria Sánchez-Puig , Orazio Nicolotti , Michele Saviano , Dritan Siliqi , Giuseppe Felice Mangiatordi Journal Of Biomolecular Structure And Dynamics DOI: 10.1080/07391102.2019.1704883 Diamond Proposal Number(s): [21741] Show Abstract ▼ Abstract: Shwachman-Diamond Syndrome (SDS) is an autosomal recessive disorder whose patients present mutations in two ribosome assembly proteins, the Shwachman-Bodian-Diamond Syndrome protein (SBDS) and the Elongation Factor-Like 1 (EFL1). Due to the lack of knowledge of the molecular mechanisms responsible for SDS pathogenesis, current therapy is nonspecific and focuses only at alleviating the symptoms. Building on the recent observation that EFL1 single-point mutations clinically manifest as SDS-like phenotype, we carried out comparative Molecular Dynamics (MD) simulations on three mutants, T127A, M882K and R1095Q and wild type EFL1. As supported by small angle X-ray scattering experiments, the obtained data improve the static EFL1 model resulting from the Cryo-electron microscopy and clearly show that all the mutants experience a peculiar rotation, around the hinge region, of domain IV with respect to domains I and II leading to a different conformation respect to that of wild type protein. This study supports the notion that EFL1 function is governed by an allosteric mechanism involving the concerted action of GTPase domain (domain I) and the domain IV and can help point towards new approaches to SDS treatment.	Dec 2019

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