Imperial College London

Dr Ernesto Cota

Faculty of Natural SciencesDepartment of Life Sciences

Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 7594 3689e.cota Website

 
 
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Location

 

601Sir Ernst Chain BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

57 results found

Pennington HG, Rhian J, Kwon S, Bonciani G, Thieron H, Chandler T, Luong P, Morgan S, Przydacz M, Bozkurt T, Wallington E, Kwaaitaal M, Panstruga R, Cota E, Spanu Pet al., 2019, The fungal ribonuclease-like effector protein CSEP0064/BEC1054 represses plant immunity and interferes with degradation of host ribosomal RNA, PLoS Pathogens, Vol: 15, ISSN: 1553-7366

The biotrophic fungal pathogen Blumeria graminis causes the powdery mildew disease of cereals and grasses. We present the first crystal structure of a B. graminis effector of pathogenicity (CSEP0064/BEC1054), demonstrating it has a ribonuclease (RNase)-like fold. This effector is part of a group of RNase-like proteins (termed RALPHs) which comprise the largest set of secreted effector candidates within the B. graminis genomes. Their exceptional abundance suggests they play crucial functions during pathogenesis. We show that transgenic expression of RALPH CSEP0064/BEC1054 increases susceptibility to infection in both monocotyledonous and dicotyledonous plants. CSEP0064/BEC1054 interacts in planta with the pathogenesis-related protein PR10. The effector protein associates with total RNA and weakly with DNA. Methyl jasmonate (MeJA) levels modulate susceptibility to aniline-induced host RNA fragmentation. In planta expression of CSEP0064/BEC1054 reduces the formation of this RNA fragment. We propose CSEP0064/BEC1054 is a pseudoenzyme that binds to host ribosomes, thereby inhibiting the action of plant ribosome-inactivating proteins (RIPs) that would otherwise lead to host cell death, an unviable interaction and demise of the fungus.

Journal article

Jamshidiha M, Pérez-Dorado I, Murray JW, Tate EW, Cota E, Read RJet al., 2019, Coping with strong translational noncrystallographic symmetry and extreme anisotropy in molecular replacement with Phaser: human Rab27a, Acta Crystallographica Section D Structural Biology, Vol: 75, Pages: 342-353, ISSN: 2059-7983

Data pathologies caused by effects such as diffraction anisotropy and translational noncrystallographic symmetry (tNCS) can dramatically complicate the solution of the crystal structures of macromolecules. Such problems were encountered in determining the structure of a mutant form of Rab27a, a member of the Rab GTPases. Mutant Rab27a constructs that crystallize in the free form were designed for use in the discovery of drugs to reduce primary tumour invasiveness and metastasis. One construct, hRab27a<jats:sup>Mut</jats:sup>, crystallized within 24 h and diffracted to 2.82 Å resolution, with a unit cell possessing room for a large number of protein copies. Initial efforts to solve the structure using molecular replacement by <jats:italic>Phaser</jats:italic> were not successful. Analysis of the data set revealed that the crystals suffered from both extreme anisotropy and strong tNCS. As a result, large numbers of reflections had estimated standard deviations that were much larger than their measured intensities and their expected intensities, revealing problems with the use of such data at the time in <jats:italic>Phaser</jats:italic>. By eliminating extremely weak reflections with the largest combined effects of anisotropy and tNCS, these problems could be avoided, allowing a molecular-replacement solution to be found. The lessons that were learned in solving this structure have guided improvements in the numerical analysis used in <jats:italic>Phaser</jats:italic>, particularly in identifying diffraction measurements that convey very little information content. The calculation of information content could also be applied as an alternative to ellipsoidal truncation. The post-mortem analysis also revealed an oversight in accounting for measurement errors in the fast rotation function. While the crystal of mutant Rab27a is not amenable to drug screening, the structure can guide new modifications to obtain more sui

Journal article

Rasheed M, Jamshidiha M, Puglisi R, Yan R, Cota E, Pastore Aet al., 2019, Structural and functional characterization of a frataxin from a thermophilic organism, FEBS Journal, Vol: 286, Pages: 495-506, ISSN: 0014-2956

Frataxins form an interesting family of iron‐binding proteins with an almost unique fold and are highly conserved from bacteria to primates. They have a pivotal role in iron–sulfur cluster biogenesis as regulators of the rates of cluster formation, as it is testified by the fact that frataxin absence is incompatible with life and reduced levels of the protein lead to the recessive neurodegenerative disease Friedreich's ataxia. Despite its importance, the structure of frataxin has been solved only from relatively few species. Here, we discuss the X‐ray structure of frataxin from the thermophilic fungus Chaetomium thermophilum, and the characterization of its interactions and dynamics in solution. We show that this eukaryotic frataxin has an unusual variation in the classical frataxin fold: the last helix is shorter than in other frataxins which results in a less symmetrical and compact structure. The stability of this protein is comparable to that of human frataxin, currently the most stable among the frataxin orthologues. We also characterized the iron‐binding mode of Ct frataxin and demonstrated that it binds it through a semiconserved negatively charged ridge on the first helix and beta‐strand. Moreover, this frataxin is also able to bind the bacterial ortholog of the desulfurase, which is central in iron–sulfur cluster synthesis, and act as its inhibitor.

Journal article

Yu J, Knoppova J, Michoux F, Bialek W, Cota Segura E, Shukla M, Straskova A, Aznar G, Sobotka R, Komenda J, Murray J, Nixon PJet al., 2018, Ycf48 involved in the biogenesis of the oxygen-evolving photosystem II complex is a seven-bladed beta-propeller protein, Proceedings of the National Academy of Sciences, Vol: 115, Pages: E7824-E7833, ISSN: 0027-8424

Robust photosynthesis in chloroplasts and cyanobacteria requires the participation of accessory proteins to facilitate the assembly and maintenance of the photosynthetic apparatus located within the thylakoid membranes. The highly conserved Ycf48 protein acts early in the biogenesis of the oxygen-evolving photosystem II (PSII) complex by binding to newly synthesized precursor D1 subunit and by promoting efficient association with the D2 protein to form a PSII reaction center (PSII RC) assembly intermediate. Ycf48 is also required for efficient replacement of damaged D1 during the repair of PSII. However, the structural features underpinning Ycf48 function remain unclear. Here we show that Ycf48 proteins encoded by the thermophilic cyanobacterium Thermosynechococcus elongatus and the red alga Cyanidioschyzon merolae form seven-bladed beta-propellers with the 19-aa insertion characteristic of eukaryotic Ycf48 located at the junction of blades 3 and 4. Knowledge of these structures has allowed us to identify a conserved “Arg patch” on the surface of Ycf48 that is important for binding of Ycf48 to PSII RCs but also to larger complexes, including trimeric photosystem I (PSI). Reduced accumulation of chlorophyll in the absence of Ycf48 and the association of Ycf48 with PSI provide evidence of a more wide-ranging role for Ycf48 in the biogenesis of the photosynthetic apparatus than previously thought. Copurification of Ycf48 with the cyanobacterial YidC protein insertase supports the involvement of Ycf48 during the cotranslational insertion of chlorophyll-binding apopolypeptides into the membrane.

Journal article

Riviere F, Dian C, Perez-Dorado I, Ritzefeld M, Shen J, Cota E, Meinnel T, Tate EW, Giglione Cet al., 2018, Mechanistic insight into HsNMT1-mediated acylation, Publisher: WILEY, Pages: 421-422, ISSN: 2211-5463

Conference paper

Zhao W, Jamshidiha M, Lanyon-Hogg T, Recchi C, Cota E, Tat EWet al., 2017, Direct targeting of the ras GTPase superfamily through structure-based design, Current Topics in Medicinal Chemistry, Vol: 17, Pages: 16-29, ISSN: 1568-0266

The Ras superfamily of small monomeric GTPases includes some of the most prominent cancer targets for which no selective therapeutic agent has yet been successfully developed. The turn of the millennium saw a resurgence of efforts to target these enzymes using new and improved biophysical techniques to overcome the perceived difficulties of insurmountably high affinity for guanosine nucleotides and flat, flexible topology lacking suitable pockets for small molecule inhibitors. Further, recent investigations have begun to probe the dynamic conformational status of GTP-bound Ras, opening up new mechanisms of inhibition. While much of the literature has focused on the oncogenic Ras proteins, particularly K-Ras, these represent only a small minority of therapeutically interesting targets within the superfamily; for example, the Rab GTPases are the largest subfamily of about 70 members, and present an as yet untapped class of potential targets. The present review documents the key methodologies employed to date in structure-guided attempts to drug the Ras GTPases, and forecasts their transferability to other similarly challenging proteins in the superfamily.

Journal article

Perez-Dorado JI, Chee SM, Hale L, Jones R, Kichik N, Tate E, Cota Eet al., 2016, Unravelling the molecular basis of adhesion to the host via Als1, a major virulence factor from Candida albicans, 41st FEBS Congress on Molecular and Systems Biology for a Better Life, Publisher: WILEY-BLACKWELL, Pages: 78-78, ISSN: 1742-464X

Conference paper

Hagiwara Y, Sieverling L, Hanif F, Anton J, Dickinson ER, Bui TTT, Andreeva A, Barran PE, Cota Segura E, Nikolova PVet al., 2016, Consequences of point mutations in melanoma-associated antigen 4 (MAGE-A4) protein: Insights from structural and biophysical studies., Scientific Reports, Vol: 6, ISSN: 2045-2322

The Melanoma-Associated Antigen A4 (MAGE-A4) protein is a target for cancer therapy. The function of this protein is not well understood. We report the first comprehensive study on key cancer-associated MAGE-A4 mutations and provide analysis on the consequences of these mutations on the structure, folding and stability of the protein. Based on Nuclear Magnetic Resonance and Circular Dichroism, these mutations had no significant effects on the structure and the folding of the protein. Some mutations affected the thermal stability of the protein remarkably. Native mass spectrometry of wild-type MAGE-A4 showed a broad charge state distribution suggestive of a structurally dynamic protein. Significant intensity was found in relatively low charge states, indicative of a predominantly globular form and some population in more extended states. The latter is supported by Ion Mobility measurements. The MAGE-A4 mutants exhibited similar features. These novel molecular insights shed further light on better understanding of these proteins, which are implicated in a wide range of human cancers.

Journal article

Moyes DL, Wilson D, Richardson JP, Mogavero S, Tang SX, Wernecke J, Hoefs S, Gratacap RL, Robbins J, Runglall M, Murciano C, Blagojevic M, Thavaraj S, Foerster TM, Hebecker B, Kasper L, Vizcay G, Iancu SI, Kichik N, Haeder A, Kurzai O, Luo T, Krueger T, Kniemeyer O, Cota E, Bader O, Wheeler RT, Gutsmann T, Hube B, Naglik JRet al., 2016, Candidalysin is a fungal peptide toxin critical for mucosal infection, Nature, Vol: 532, Pages: 64-68, ISSN: 0028-0836

Journal article

Hoyer LL, Cota E, 2016, Candida albicans agglutinin-like sequence (aIs) family vignettes: a review of aIs protein structure and function, Frontiers in Microbiology, Vol: 7, ISSN: 1664-302X

Approximately two decades have passed since the description of the first gene inthe Candida albicans ALS (agglutinin-like sequence) family. Since that time, much hasbeen learned about the composition of the family and the function of its encoded cellsurfaceglycoproteins. Solution of the structure of the Als adhesive domain providesthe opportunity to evaluate the molecular basis for protein function. This review articleis formatted as a series of fundamental questions and explores the diversity of the Alsproteins, as well as their role in ligand binding, aggregative effects, and attachment toabiotic surfaces. Interaction of Als proteins with each other, their functional equivalence,and the effects of protein abundance on phenotypic conclusions are also examined.Structural features of Als proteins that may facilitate invasive function are considered.Conclusions that are firmly supported by the literature are presented while highlightingareas that require additional investigation to reveal basic features of the Als proteins,their relatedness to each other, and their roles in C. albicans biology.

Journal article

Cota E, Hoyer LL, 2015, The Candida albicans agglutinin-like sequence family of adhesins: functional insights gained from structural analysis, Future Microbiology, Vol: 10, Pages: 1635-1648, ISSN: 1746-0921

Candida albicans colonizes many host sites suggesting its interaction with diverse ligands.Candida albicans adhesion is mediated by a number of proteins including those in the Als(agglutinin-like sequence) family, which have been studied intensively. The recent solutionof the Als binding domain structure ended years of speculation regarding the molecularmechanism for Als adhesive function. Als adhesins bind flexible C termini from a broadcollection of proteins, providing the basis for adhesion to various cell types and perhaps forC. albicans broad tissue tropism. Understanding adhesive functions at the molecular level willreveal the sequence of events in C. albicans pathogenesis, from host recognition to complexinteractions such as development of polymicrobial biofilms or disseminated disease.

Journal article

Yusuf NA, Green JL, Wall RJ, Knuepfer E, Moon RW, Schulte-Huxel C, Stanway RR, Martin SR, Howell SA, Douse CH, Cota E, Tate EW, Tewari R, Holder AAet al., 2015, The Plasmodium Class XIV Myosin, MyoB, Has a Distinct Subcellular Location in Invasive and Motile Stages of the Malaria Parasite and an Unusual Light Chain, Journal of Biological Chemistry, Vol: 290, Pages: 12147-12164, ISSN: 1083-351X

Myosin B (MyoB) is one of the two short class XIV myosinsencoded in the Plasmodium genome. Class XIV myosins arecharacterized by a catalytic “head,” a modified “neck,” and theabsence of a “tail” region. Myosin A (MyoA), the other class XIVmyosin in Plasmodium, has been established as a component ofthe glideosome complex important in motility and cell invasion,but MyoB is not well characterized. We analyzed the propertiesof MyoB using three parasite species as follows: Plasmodiumfalciparum, Plasmodium berghei, and Plasmodium knowlesi.MyoB is expressed in all invasive stages (merozoites, ookinetes,and sporozoites) of the life cycle, and the protein is found in adiscrete apical location in these polarized cells. In P. falciparum,MyoB is synthesized very late in schizogony/merogony, and itslocation in merozoites is distinct from, and anterior to, that of arange of known proteins present in the rhoptries, rhoptry neckor micronemes. Unlike MyoA, MyoB is not associated withglideosome complex proteins, including the MyoA light chain,myosin A tail domain-interacting protein (MTIP). A uniqueMyoB light chain (MLC-B) was identified that contains a calmodulin-likedomain at the C terminus and an extended N-terminalregion. MLC-B localizes to the same extreme apical polein the cell as MyoB, and the two proteins form a complex. Wepropose that MLC-B is a MyoB-specific light chain, and for theshort class XIV myosins that lack a tail region, the atypical myosinlight chains may fulfill that role.

Journal article

Douse CH, Vrielink N, Zhang W, Cota E, Tate EWet al., 2015, Targeting a Dynamic Protein-Protein Interaction: Fragment Screening against the Malaria Myosin A Motor Complex, CHEMMEDCHEM, Vol: 10, Pages: 134-143, ISSN: 1860-7179

Journal article

Hoyer LL, Oh S-H, Jones R, Cota Eet al., 2014, A proposed mechanism for the interaction between the Candida albicans Als3 adhesin and streptococcal cell wall proteins, Frontiers in Microbiology, Vol: 5, ISSN: 1664-302X

C. albicans binds various bacteria, including the oral commensal Streptococcus gordonii. Published reports documented the role of C. albicans Als3 and S. gordonii SspB in this interaction, and the importance of the Als N-terminal domain (NT-Als) in C. albicans adhesion. Here, we demonstrate that Als1 also binds S. gordonii. We also describe use of the NT-Als crystal structure to design mutations that precisely disrupt peptide-binding cavity (PBC) or amyloid-forming region (AFR) function in Als3. C. albicans displaying Als3 PBC mutant proteins showed significantly reduced binding to S. gordonii; mutation of the AFR did not affect the interaction. These observations present an enigma: the Als PBC binds free C termini of ligands, but the SspB C terminus is covalently linked to peptidoglycan and thus unavailable as a ligand. These observations and the predicted SspB elongated structure suggest that partial proteolysis of streptococcal cell wall proteins is necessary for recognition by Als adhesins.

Journal article

Douse CH, Maas SJ, Thomas JC, Garnett JA, Sun Y, Cota E, Tate EWet al., 2014, Crystal Structures of Stapled and Hydrogen Bond Surrogate Peptides Targeting a Fully Buried Protein-Helix Interaction, ACS CHEMICAL BIOLOGY, Vol: 9, Pages: 2204-2209, ISSN: 1554-8929

Journal article

Berry AA, Yang Y, Pakharukova N, Garnett JA, Lee W-C, Cota E, Marchant J, Roy S, Tuittila M, Liu B, Inman KG, Ruiz-Perez F, Mandomando I, Nataro JP, Zavialov AV, Matthews Set al., 2014, Structural Insight into Host Recognition by Aggregative Adherence Fimbriae of Enteroaggregative Escherichia coli, PLOS PATHOGENS, Vol: 10, ISSN: 1553-7366

Journal article

Lin J, Oh S-H, Jones R, Garnett JA, Salgado PS, Rusnakova S, Matthews SJ, Hoyer LL, Cota Eet al., 2014, The Peptide-binding Cavity Is Essential for Als3-mediated Adhesion of Candida albicans to Human Cells, Journal of Biological Chemistry, Vol: 289, Pages: 18401-18412, ISSN: 1083-351X

Background: Of the eight cell surface glycoproteins in the C. albicans Als family, Als3 makes the largest contribution to adhesion to human cells.Results: Mutation of the Als3 peptide-binding cavity (PBC) results in loss of Als3 adhesive function.Conclusion: The PBC is required for Als3 adhesive function.Significance: Interfering with PBC function is a viable strategy for inhibiting C. albicans adhesion.

Journal article

Douse CH, Green JL, Salgado PS, Simpson PJ, Thomas JC, Langsley G, Holder AA, Tate EW, Cota Eet al., 2012, Regulation of the Plasmodium motor complex: phosphorylation of myosin A tail-interacting protein (MTIP) loosens its grip on MyoA., Journal of Biological Chemistry, Vol: 287, Pages: 36968-36977, ISSN: 1083-351X

Background: Recent phosphoproteome data reveal the extent of post-translational phosphorylation in selected apicomplexanparasites.Results: Binding site mutants that mimic the effect of MTIP phosphorylation in vivo severely decrease MyoA binding.Conclusion: Phosphorylation of selected binding site residues modulates the activity of the actomyosin motor.Significance: Study of Apicomplexa phosphosites can inform on the regulation of functions involved in pathogenesis.

Journal article

James E, Liu M, Sheppard C, Mekler V, Camara B, Liu B, Simpson P, Cota E, Severinov K, Matthews S, Wigneshweraraj Set al., 2012, Structural and Mechanistic Basis for the Inhibition of Escherichia coli RNA Polymerase by T7 Gp2, MOLECULAR CELL, Vol: 47, Pages: 755-766, ISSN: 1097-2765

Journal article

Moyes DL, Murciano C, Tang S, Bader O, Moran G, Cota E, Waechtler B, Wilson D, Hube B, Naglik JRet al., 2012, Epithelial responses to Candida albicans, MYCOSES, Vol: 55, Pages: 2-3, ISSN: 0933-7407

Journal article

Liu B, Garnett JA, Lee W-C, Lin J, Salgado P, Taylor J, Xu Y, Lambert S, Cota E, Matthews Set al., 2012, Promoting crystallisation of the Salmonella enteritidis fimbriae 14 pilin SefD using deuterium oxide, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol: 421, Pages: 208-213, ISSN: 0006-291X

Journal article

Simpson PJ, Cota E, Bolanos-Garcia VM, 2012, H-1, C-13 and N-15 resonance assignments of the kinetochore localisation domain of BUBR1, a central component of the spindle assembly checkpoint, BIOMOLECULAR NMR ASSIGNMENTS, Vol: 6, Pages: 115-118, ISSN: 1874-2718

Journal article

Garnett JA, Martinez-Santos VI, Saldana Z, Pape T, Hawthorne W, Chan J, Simpson PJ, Cota E, Puente JL, Giron JA, Matthews Set al., 2012, Structural insights into the biogenesis and biofilm formation by the Escherichia coli common pilus, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 109, Pages: 3950-3955, ISSN: 0027-8424

Journal article

Garnett JA, Simpson PJ, Taylor J, Benjamin SV, Tagliaferri C, Cota E, Chen Y-YM, Wu H, Matthews Set al., 2012, Structural insight into the role of Streptococcus parasanguinis Fap1 within oral biofilm formation, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol: 417, Pages: 421-426, ISSN: 0006-291X

Journal article

Cota E, 2012, Candida albicans Als adhesins - New insights from recent structural and functional data, 11th ASM Conference on Candida and Candidiasis

Conference paper

Salek-Ardakani S, Cota E, Bignell E, 2012, Host-fungal interactions: key players of antifungal immunity., Expert Rev Anti Infect Ther, Vol: 10(2), Pages: 149-151

Journal article

Bolanos-Garcia VM, Lischetti T, Matak-Vinkovic D, Cota E, Simpson PJ, Chirgadze DY, Spring DR, Robinson CV, Nilsson J, Blundell TLet al., 2011, Structure of a Blinkin-BUBR1 Complex Reveals an Interaction Crucial for Kinetochore-Mitotic Checkpoint Regulation via an Unanticipated Binding Site (vol 19, pg 1691, 2011), Structure, Vol: 19, Pages: 1895-1895, ISSN: 1878-4186

Journal article

Bolanos-Garcia VM, Lischetti T, Matak-Vinkovic D, Cota E, Simpson PJ, Chirgadze DY, Spring DR, Robinson CV, Nilsson J, Blundell TLet al., 2011, Structure of a Blinkin-BUBR1 Complex Reveals an Interaction Crucial for Kinetochore-Mitotic Checkpoint Regulation via an Unanticipated Binding Site, STRUCTURE, Vol: 19, Pages: 1691-1700, ISSN: 0969-2126

Journal article

Sheppard C, Camara B, Shadrin A, Akulenko N, Liu M, Baldwin G, Severinov K, Cota E, Matthews S, Wigneshweraraj SRet al., 2011, Reprint of: Inhibition of Escherichia coli RNAp by T7 Gp2 protein: Role of Negatively Charged Strip of Amino Acid Residues in Gp2, JOURNAL OF MOLECULAR BIOLOGY, Vol: 412, Pages: 832-841, ISSN: 0022-2836

Journal article

Salgado PS, Yan R, Taylor JD, Burchell L, Jones R, Hoyer LL, Matthews SJ, Simpson PJ, Cota Eet al., 2011, Structural basis for the broad specificity to host-cell ligands by the pathogenic fungus Candida albicans, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 108, Pages: 15775-15779, ISSN: 0027-8424

Journal article

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