Leyton Group - Assembly, function, and applications of nanoscale bacterial surface structures

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Autotransporters are a large family of virulence proteins produced by Gram-negative bacterial pathogens responsible for infectious diseases such as diarrhoea, whooping cough, cholera, chlamydia, and bacterial meningitis. Autotransporters help establish infection and contribute to disease by performing a vast array of effector functions, including adhesion and invasion of, and cytotoxicity towards eukaryotic host cells, biofilm formation, and disruption of the host immune system. Our research is focused on understanding how autotransporters are assembled into bacterial outer membranes, and how they function to mediate infection and disease once they get there. We are also interested in reengineering autotransporters as recombinant protein production devices for use in basic research, biotechnology, or pharmaceutical applications.

Membrane transporters and channels

Group Leader

Denisse Leyton

PhB Student

Hugh Wilson

PhD Students

Special Project Student

Harrish Siva Vasudevan

Project	Status
Functional characterisation of novel autotransporter proteins	Current
Redesign and engineering of the autotransporter β-barrel domain	Current
To what degree does autotransporter folding inside the bacterial cell resemble autotransporter folding in bulk solution?	Current

Selected publications

Xiaojun Yuan, Matthew D. Johnson, Jing Zhang, Alvin W. Lo, Mark A. Schembri, Lakshmi C. Wijeyewickrema, Robert N. Pike, Gerard H. M. Huysmans, Ian R. Henderson & Denisse L. Leyton (2018). Molecular basis for the folding of B-helical autotransporter passendger domains. Nature Communications 9:1395 doi: 10.1038/ s41467-018-03593-2
Drobnak I, Braselmann E, Chaney JL, Leyton DL, Bernstein HD, Lithgow T, Luirink J, Nataro JP, Clark PL (2014). Of linkers and autochaperones: An unambiguous nomenclature to identify common and uncommon themes for autotransporter secretion. Molecular Microbiology doi: 10.1111/mmi.12838.
Shen HH, Leyton DL, Shiota T, Belousoff MJ, Noinaj N, Lu J, Holt SA, Tan K, Selkrig J, Webb CT, Buchanan SK, Martin LL and Lithgow T (2014). Reconstitution of a nanomachine driving the assembly of proteins into bacterial outer membranes. Nature Communications 5:5078. doi: 10.1038/ncomms6078.
Leyton DL, Johnson MD, Thapa R, Huysmans GHM, Dunstan RA, Celik N, Shen H, Loo D, Belousoff MJ, Purcell AW, Henderson IR, Beddoe T, Rossjohn J, Martin LL, Strugnell RA, Lithgow T (2014). A mortise-tenon joint in the transmembrane domain modulates autotransporter assembly into bacterial outer membranes. Nature Communications 5:4239. doi: 10.1038/ncomms5239.
Selkrig J, Leyton DL, Webb CT, Lithgow T (2013). Assembly of β-barrel proteins into bacterial outer membranes. Biochimica et Biophysica Acta-Molecular Cell Research pii: S0167-4889(13)00354-6. doi: 10.1016/j.bbamcr.2013.10. 009.
Celik N, Webb CT, Leyton DL, Holt KE, Heinz E, Gorrell R, Kwok T, Naderer T, Strugnell RA, Speed TP, Teasdale RD, Likic VA, Lithgow T (2012). A bioinformatic strategy for the detection, classification and analysis of bacterial autotransporters. PLoS One 7(8):e43245. doi: 10.1371/journal.pone.0043245.
Sevastsyanovich YR, Leyton DL, Wells TJ, Wardius CA, Tveen-Jensen K, Morris FC, Knowles TJ, Cunningham AF, Cole JA, Henderson IR (2012). A generalised module for the selective extracellular accumulation of recombinant proteins. Microbial Cell Factories 11:69. doi: 10.1186/1475-2859-11-69.
Selkrig J, Mosbahi K, Webb CT, Belousoff MJ, Perry AJ, Wells TJ, Morris FC, Leyton DL, Totsika M, Phan M, Celik N, Kelly M, Oates C, Hartland EL, Robins-Browne RM, Harsha Ramarathinam S, Purcell AW, Schembri MA, Strugnell RA, Henderson IR, Walker D, Lithgow T (2012). Discovery of an archetypal protein transport system in bacterial outer membranes. Nature Structural & Molecular Biology Apr 1. doi: 10.1038/nsmb.2261.
Leyton DL, Rossiter AE, Henderson IR (2012). From self sufficiency to dependence: mechanisms and factors important for autotransporter biogenesis. Nature Reviews Microbiology 10; 213-25.
Leyton DL, Sevastsyanovich YR, Browning DF, Rossiter AE, Wells TJ, Fitzpatrick RE, Overduin M, Cunningham AF, Henderson IR (2011). Size and conformation limits to secretion of disulfide-bonded loops in autotransporter proteins. Journal of Biological Chemistry 286; 42283-91.
Raghunathan D, Wells TJ, Morris FC, Shaw RK, Bobat S, Peters SE, Paterson GK, Jensen KT, Leyton DL, Blair JM, Browning DF, Pravin J, Flores-Langarica A, Hitchcock JR, Moraes CT, Piazza RM, Maskell DJ, Webber MA, May RC, MacLennan CA, Piddock LJ, Cunningham AF, Henderson IR (2011). SadA, a trimeric autotransporter from Salmonella enterica serovar Typhimurium, can promote biofilm formation and provides limited protection against infection. Infection and Immunity 79; 4342-52.
Rossiter AE*, Leyton DL*, Tveen-Jensen K, Browning DF, Sevastsyanovich Y, Knowles TJ, Nichols KB, Cunningham AF, Overduin M, Schembri MA, Henderson IR (2011). The essential β-barrel assembly machinery complex components BamD and BamA are required for autotransporter biogenesis. Journal of Bacteriology 193; 4250-3. *these authors contributed equally
Rossiter AE, Browning DF, Leyton DL, Johnson MD, Godfrey RE, Wardius CA, Desvaux M, Cunningham AF, Ruiz-Perez F, Nataro JP, Busby SJ, Henderson IR (2011). Transcription of the plasmid-encoded toxin gene from enteroaggregative Escherichia coli is regulated by a novel co-activation mechanism involving CRP and Fis. Molecular Microbiology 81:179-91.
Knowles TJ, Browning DF, Jeeves M, Maderbocus R, Rajesh S, Sridhar P, Manoli E, Emery D, Sommer U, Spencer A, Leyton DL, Squire D, Chaudhuri RR, Viant M, Cunningham AF, Henderson IR and Overduin M (2011). Structure and function of BamE within the outer membrane and the β-barrel assembly machine. EMBO Reports 12; 123-128.
Tsai JC, Yen M, Castillo R, Leyton DL, Henderson IR and Saier, Jr. MH (2010). Phylogenetic analyses reveal the Bacterial Intimins and Invasins are a large and novel family of secreted proteins. PLoS One, 5; e14403.
Leyton DL, Luna MG, Sevastsyanovich YR, Jensen KT, Browning DF, Scott-Tucker A and Henderson IR (2010). The unusual extended signal peptide region is not required for secretion and function of an Escherichia coli autotransporter. FEMS Microbiology Letters 311: 133-139.
Chaudhuri RR, Sebaihia M, Hobman JL, Webber MA, Leyton DL, Goldberg MD, Cunningham AF, Scott-Tucker A, Ferguson PR, Thomas CM, Frankel G, Tang CM, Dudley EG, Roberts IS, Rasko DA, Pallen MJ, Parkhill J, Nataro JP, Thomson NR and Henderson IR (2010). Complete Genome Sequence and Comparative Metabolic Profiling of the Prototypical Enteroaggregative Escherichia coli Strain 042. PLoS One, 5; e8801.
Ruiz-Perez F, Henderson IR, Leyton DL, Rossiter AE, Zhang Y and Nataro JP (2009). Roles of periplasmic chaperone proteins in the biogenesis of serine protease autotransporters of Enterobacteriaceae. Journal of Bacteriology 191; 6571-6583.
Leyton DL, Adams LM, Kelly M, Sloan J, Tauschek M, Robins-Browne RM and Hartland EL (2007). Contribution of a novel gene rpeA encoding a putative autotransporter adhesin to intestinal colonization by rabbit enteropathogenic Escherichia coli. Infection and Immunity 75; 4664-4669.
Leyton DL, Sloan J, Hill RE, Doughty S and Hartland EL (2003). Transfer region of pO113 from enterohemorrhagic Escherichia coli: Similarity with R64 and Identification of a novel plasmid-encoded autotransporter, EpeA. Infection and Immunity 71; 6307-6319.