Imperial College London

DrMichalBarski

Faculty of MedicineDepartment of Infectious Disease

Research Associate
 
 
 
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Contact

 

+44 (0)20 7594 3838m.barski

 
 
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Location

 

313Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

7 results found

Barski M, Minnell J, Pye V, Nans A, Hodakova Z, Cherepanov P, Maertens Get al., 2020, Cryo-EM structure of the deltaretroviral intasome in complex with the PP2A regulatory subunit B56γ, Nature Communications, Vol: 11, ISSN: 2041-1723

Human T-cell lymphotropic virus type 1 (HTLV-1) is a deltaretrovirus and the most oncogenic pathogen. Many of the ~20 million HTLV-1 infected people will develop severe leukaemia or an ALS-like motor disease, unless a therapy becomes available. A key step in the establishment of infection is the integration of viral genetic material into the host genome, catalysed by the retroviral integrase (IN) enzyme. Here, we use X-ray crystallography and single-particle cryo-electron microscopy to determine the structure of the functional deltaretroviral IN assembled on viral DNA ends and bound to the B56γ subunit of its human host factor, protein phosphatase 2 A. The structure reveals a tetrameric IN assembly bound to two molecules of the phosphatase via a conserved short linear motif. Insight into the deltaretroviral intasome and its interaction with the host will be crucial for understanding the pattern of integration events in infected individuals and therefore bears important clinical implications.

Journal article

Barski MS, Minnell JJ, Maertens G, 2019, Inhibition of HTLV-1 infection by HIV-1 first- and second-generation integrase strand transfer inhibitors, Frontiers in Microbiology, Vol: 10, ISSN: 1664-302X

More than 10 million people worldwide are infected with the retrovirus human T-cell lymphotropic virus type 1 (HTLV-1). Infection phenotypes can range from asymptomatic to severe adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy. HTLV-1, like human immunodeficiency virus type 1 (HIV-1), is a blood-borne pathogen and viral infection happens in a similar fashion, with the major mode of transmission through breastfeeding. There is a strong correlation between time of infection and disease development, with a higher incidence of ATLL in patients infected during childhood. There is no successful therapeutic or preventative regimen for HTLV-1. It is therefore essential to develop therapies to inhibit transmission or block the onset/development of HTLV-1 associated diseases. Recently, we have seen the overwhelming success of integrase strand transfer inhibitors (INSTIs) in the treatment of HIV-1. Previously, raltegravir was shown to inhibit HTLV-1 infection. Here, we tested FDA-approved and two Phase II HIV-1 INSTIs in vitro and in a cell-to-cell infection model and show that they are highly active in blocking HTLV-1 infection, with bictegravir (EC50 = 0.30 ± 0.17 nM) performing best overall. INSTIs, in particular bictegravir, are more potent in blocking HTLV-1 transmission than tenofovir disproxil fumarate, an RT inhibitor. Our data suggest that HIV-1 INSTIs could present a good clinical strategy in HTLV-1 management and justifies the inclusion of INSTIs in clinical trials.

Journal article

Barski M, 2018, BASILIScan: a tool for high-throughput analysis of intrinsic disorder patterns in homologous proteins, BMC Genomics, Vol: 19, ISSN: 1471-2164

BackgroundIntrinsic structural disorder is a common property of many proteins, especially in eukaryotic and virus proteomes. The tendency of some proteins or protein regions to exist in a disordered state usually precludes their structural characterisation and renders them especially difficult for experimental handling after recombinant expression.ResultsA new intuitive, publicly-available computational resource, called BASILIScan, is presented here. It provides a BLAST-based search for close homologues of the protein of interest, integrated with a simultaneous prediction of intrinsic disorder together with a robust data viewer and interpreter. This allows for a quick, high-throughput screening, scoring and selection of closely-related yet highly structured homologues of the protein of interest. Comparative parallel analysis of the conservation of extended regions of disorder in multiple sequences is also offered. The use of BASILIScan and its capacity for yielding biologically applicable predictions is demonstrated. Using a high-throughput BASILIScan screen it is also shown that a large proportion of the human proteome displays homologous sequences of superior intrinsic structural order in many related species.ConclusionThrough the swift identification of intrinsically stable homologues and poorly conserved disordered regions by the BASILIScan software, the chances of successful recombinant protein expression and compatibility with downstream applications such as crystallisation can be greatly increased.

Journal article

Barski M, 2018, BASILIScan: a tool for high-throughput analysis of intrinsic disorder patterns in homologous proteins

Background: Intrinsic structural disorder is a common property of many proteins, especially in eukaryotic and virus proteomes. The tendency of some proteins or protein regions to exist in a disordered state usually precludes their structural characterisation and renders them especially difficult for experimental handling after recombinant expression. Results: A new intuitive, publicly-available computational resource, called BASILIScan, is presented here. It provides a BLAST-based search for close homologues of the protein of interest, integrated with a simultaneous prediction of intrinsic disorder together with a robust data viewer and interpreter. This allows for a quick, high-throughput screening, scoring and selection of closely-related yet highly structured homologues of the protein of interest. Comparative parallel analysis of the conservation of extended regions of disorder in multiple sequences is also offered. The use of BASILIScan and its capacity for yielding biologically applicable predictions is demonstrated. Using a high-throughput BASILIScan screen it is also shown that a large proportion of the human proteome displays homologous sequences of superior intrinsic structural order in many related species. Conclusion: Through the swift identification of intrinsically stable homologues and poorly conserved disordered regions by the BASILIScan software, the chances of successful recombinant protein expression and compatibility with downstream applications such as crystallisation can be greatly increased.

Working paper

Barski M, Brennan B, Miller OK, Potter JA, Vijayakrishnan S, Bhella D, Naismith JH, Elliott RM, Schwarz-Linek Uet al., 2017, Rift Valley fever phlebovirus NSs protein core domain structure suggests molecular basis for nuclear filaments., eLife, Vol: 6, ISSN: 2050-084X

Rift Valley fever phlebovirus (RVFV) is a clinically and economically important pathogen increasingly likely to cause widespread epidemics. RVFV virulence depends on the interferon antagonist non-structural protein (NSs), which remains poorly characterized. We identified a stable core domain of RVFV NSs (residues 83-248), and solved its crystal structure, a novel all-helical fold organized into highly ordered fibrils. A hallmark of RVFV pathology is NSs filament formation in infected cell nuclei. Recombinant virus encoding the NSs core domain induced intranuclear filaments, suggesting it contains all essential determinants for nuclear translocation and filament formation. Mutations of key crystal fibril interface residues in viruses encoding full-length NSs completely abrogated intranuclear filament formation in infected cells. We propose the fibrillar arrangement of the NSs core domain in crystals reveals the molecular basis of assembly of this key virulence factor in cell nuclei. Our findings have important implications for fundamental understanding of RVFV virulence.

Journal article

Barski MS, 2015, Facing down emerging viruses: a better knowledge of the pathogenesis of emerging zoonotic diseases is crucial if we want to prepare for "the next ebola"., The Scientist

Journal article

Barski M, 2015, Facing Down Emerging Viruses, SCIENTIST, Vol: 29, Pages: 27-28, ISSN: 0890-3670

Journal article

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