Imperial College London

DrMatthewChild

Faculty of Natural SciencesDepartment of Life Sciences

Research Fellow (Sir Henry Dale Fellow)
 
 
 
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Contact

 

+44 (0)20 7594 5402m.child Website

 
 
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Location

 

612Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
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17 results found

Anderson DP, Benns HJ, Tate EW, Child MAet al., 2020, CRISPR-TAPE: protein-centricCRISPRguide design for targeted proteome engineering, MOLECULAR SYSTEMS BIOLOGY, Vol: 16, ISSN: 1744-4292

Journal article

Anderson DP, Benns HJ, Tate EW, Child MAet al., 2020, CRISPR-TAPE: protein-centric CRISPR guide design for targeted proteome engineering., Mol Syst Biol, Vol: 16

Rational molecular engineering of proteins with CRISPR-based approaches is challenged by the gene-centric nature of gRNA design tools. To address this, we have developed CRISPR-TAPE, a protein-centric gRNA design algorithm that allows users to target specific residues, or amino acid types within proteins. gRNA outputs can be customized to support maximal efficacy of homology-directed repair for engineering purposes, removing time-consuming post hoc curation, simplifying gRNA outputs and reducing CPU times.

Journal article

Benns HJ, Tate EW, Child MA, 2018, Activity-Based Protein Profiling for the Study of Parasite Biology., Curr Top Microbiol Immunol, Vol: 420, Pages: 155-174, ISSN: 0070-217X

Parasites exist within most ecological niches, often transitioning through biologically and chemically complex host environments over the course of their parasitic life cycles. While the development of technologies for genetic engineering has revolutionised the field of functional genomics, parasites have historically been less amenable to such modification. In light of this, parasitologists have often been at the forefront of adopting new small-molecule technologies, repurposing drugs into biological tools and probes. Over the last decade, activity-based protein profiling (ABPP) has evolved into a powerful and versatile chemical proteomic platform for characterising the function of enzymes. Central to ABPP is the use of activity-based probes (ABPs), which covalently modify the active sites of enzyme classes ranging from serine hydrolases to glycosidases. The application of ABPP to cellular systems has contributed vastly to our knowledge on the fundamental biology of a diverse range of organisms and has facilitated the identification of potential drug targets in many pathogens. In this chapter, we provide a comprehensive review on the different forms of ABPP that have been successfully applied to parasite systems, and highlight key biological insights that have been enabled through their application.

Journal article

Garland M, Schulze CJ, Foe IT, van der Linden WA, Child MA, Bogyo Met al., 2018, Development of an activity-based probe for acyl-protein thioesterases, PLOS ONE, Vol: 13, ISSN: 1932-6203

Journal article

Child MA, Garland M, Foe I, Madzelan P, Treeck M, van der Linden WA, Bender KO, Weerapana E, Wilson MA, Boothroyd JC, Reese ML, Bogyo Met al., 2017, Toxoplasma DJ-1 Regulates Organelle Secretion by a Direct Interaction with Calcium-Dependent Protein Kinase 1, mBio, Vol: 8, ISSN: 2150-7511

Human DJ-1 is a highly conserved and yet functionally enigmatic protein associated with a heritable form of Parkinson’s disease. It has been suggested to be a redox-dependent regulatory scaffold, binding to proteins to modulate their function. Here we present the X-ray crystal structure of the Toxoplasma orthologue Toxoplasma gondii DJ-1 (TgDJ-1) at 2.1-Å resolution and show that it directly associates with calcium-dependent protein kinase 1 (CDPK1). The TgDJ-1 structure identifies an orthologously conserved arginine dyad that acts as a phospho-gatekeeper motif to control complex formation. We determined that the binding of TgDJ-1 to CDPK1 is sensitive to oxidation and calcium, and that this interaction potentiates CDPK1 kinase activity. Finally, we show that genetic deletion of TgDJ-1 results in upregulation of CDPK1 expression and that disruption of the CDPK1/TgDJ-1 complex in vivo prevents normal exocytosis of parasite virulence-associated organelles called micronemes. Overall, our data suggest that TgDJ-1 functions as a noncanonical kinase-regulatory scaffold that integrates multiple intracellular signals to tune microneme exocytosis in T. gondii.IMPORTANCE Apicomplexan parasites such as Toxoplasma and Plasmodium are obligate intracellular parasites that require the protective environment of a host cell in order to replicate and survive within a host organism. These parasites secrete effector proteins from specialized apical organelles to select and invade a chosen host cell. The secretion of these organelles is a tightly regulated process coordinated by endogenous small molecules and calcium-dependent protein kinases. We previously identified the Toxoplasma orthologue of the highly conserved protein DJ-1 as a regulator of microneme secretion, but the molecular basis for this was not known. We have now identified the molecular mechanism for how TgDJ-1 regulates microneme secretion. TgDJ-1 interacts with the kinase responsible for the secretion of the

Journal article

Foe IT, Child MA, Majmudar JD, Krishnamurthy S, van der Linden WA, Ward GE, Martin BR, Bogyo Met al., 2015, Global Analysis of Palmitoylated Proteins in Toxoplasma gondii, CELL HOST & MICROBE, Vol: 18, Pages: 501-511, ISSN: 1931-3128

Journal article

Bender KO, Garland M, Ferreyra JA, Hryckowian AJ, Child MA, Puri AW, Solow-Cordero DE, Higginbottom SK, Segal E, Banaei N, Shen A, Sonnenburg JL, Bogyo Met al., 2015, A small-molecule antivirulence agent for treating Clostridium difficile infection, SCIENCE TRANSLATIONAL MEDICINE, Vol: 7, ISSN: 1946-6234

Journal article

van der Linden WA, Segal E, Child MA, Byzia A, Drag M, Bogyo Met al., 2015, Design and Synthesis of Activity-Based Probes and Inhibitors for Bleomycin Hydrolase, CHEMISTRY & BIOLOGY, Vol: 22, Pages: 995-1001, ISSN: 1074-5521

Journal article

Treeck M, Sanders JL, Gaji RY, LaFavers KA, Child MA, Arrizabalaga G, Elias JE, Boothroyd JCet al., 2014, The Calcium-Dependent Protein Kinase 3 of Toxoplasma Influences Basal Calcium Levels and Functions beyond Egress as Revealed by Quantitative Phosphoproteome Analysis, PLOS PATHOGENS, Vol: 10, ISSN: 1553-7366

Journal article

Child MA, 2013, Chemical biology approaches for the study of apicomplexan parasites, MOLECULAR AND BIOCHEMICAL PARASITOLOGY, Vol: 192, Pages: 1-9, ISSN: 0166-6851

Journal article

Child MA, Hall CI, Beck JR, Ofori LO, Albrow VE, Garland M, Bowyer PW, Bradley PJ, Powers JC, Boothroyd JC, Weerapana E, Bogyo Met al., 2013, Small-molecule inhibition of a depalmitoylase enhances Toxoplasma host-cell invasion, NATURE CHEMICAL BIOLOGY, Vol: 9, Pages: 651-656, ISSN: 1552-4450

Journal article

Child MA, Harris PK, Collins CR, Withers-Martinez C, Yeoh S, Blackman MJet al., 2013, Molecular Determinants for Subcellular Trafficking of the Malarial Sheddase PfSUB2, TRAFFIC, Vol: 14, Pages: 1053-1064, ISSN: 1398-9219

Journal article

Child MA, Hall CI, Beck JR, Ofori LO, Albrow VE, Garland M, Bowyer PW, Bradley PJ, Powers JC, Boothroyd JC, Weerapana E, Bogyo Met al., 2013, Small-molecule inhibition of a depalmitoylase enhances Toxoplasma host-cell invasion., Nat Chem Biol, Vol: 9, Pages: 651-656

Although there have been numerous advances in our understanding of how apicomplexan parasites such as Toxoplasma gondii enter host cells, many of the signaling pathways and enzymes involved in the organization of invasion mediators remain poorly defined. We recently performed a forward chemical-genetic screen in T. gondii and identified compounds that markedly enhanced infectivity. Although molecular dissection of invasion has benefited from the use of small-molecule inhibitors, the mechanisms underlying induction of invasion by small-molecule enhancers have never been described. Here we identify the Toxoplasma ortholog of human APT1, palmitoyl protein thioesterase-1 (TgPPT1), as the target of one class of small-molecule enhancers. Inhibition of this uncharacterized thioesterase triggered secretion of invasion-associated organelles, increased motility and enhanced the invasive capacity of tachyzoites. We demonstrate that TgPPT1 is a bona fide depalmitoylase, thereby establishing an important role for dynamic and reversible palmitoylation in host-cell invasion by T. gondii.

Journal article

Li H, Child MA, Bogyo M, 2012, Proteases as regulators of pathogenesis: Examples from the Apicomplexa, BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, Vol: 1824, Pages: 177-185, ISSN: 1570-9639

Journal article

Hall CI, Reese ML, Weerapana E, Child MA, Bowyer PW, Albrow VE, Haraldsen JD, Phillips MR, Sandoval ED, Ward GE, Cravatt BF, Boothroyd JC, Bogyo Met al., 2011, Chemical genetic screen identifies Toxoplasma DJ-1 as a regulator of parasite secretion, attachment, and invasion, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 108, Pages: 10568-10573, ISSN: 0027-8424

Journal article

Child MA, Epp C, Bujard H, Blackman MJet al., 2010, Regulated maturation of malaria merozoite surface protein-1 is essential for parasite growth, MOLECULAR MICROBIOLOGY, Vol: 78, Pages: 187-202, ISSN: 0950-382X

Journal article

Koussis K, Withers-Martinez C, Yeoh S, Child M, Hackett F, Knuepfer E, Juliano L, Woehlbier U, Bujard H, Blackman MJet al., 2009, A multifunctional serine protease primes the malaria parasite for red blood cell invasion, EMBO JOURNAL, Vol: 28, Pages: 725-735, ISSN: 0261-4189

Journal article

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