Taylor, Maureen - Imperial College London - Department of Life Sciences, Biochemistry and Biotechnology

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Taylor, Maureen Dr 收藏完善纠错
Imperial College London Department of Life Sciences, Biochemistry and Biotechnology
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个人简介

Molecular function of sugar-binding receptors in cellular recognition events Specific arrangements of sugars decorate the surfaces of cells and are attached to proteins released from cells into the circulation and other extracellular spaces. These glycans serve as recognition signals that are bound by special receptors. In animals, many of these receptors bind to endogenous carbohydrate structures, forming the basis for cell-cell adhesion and for the selective removal of proteins from circulation. Other receptors bind foreign carbohydrates on the surfaces of potentially pathogenic micro-organisms and form part of the innate, antibody-independent immune system. Many sugar-binding receptors contain related carbohydrate-recognition domains and mutations in some of these proteins are associated with susceptibility to disease. This research is a joint project with Professor Kurt Drickamer, who is also in the Division of Molecular Biosciences. A combination of biochemical, biophysical and molecular biological approaches allows us to understand how carbohydrate-recognition domains work together to provide selective recognition of glycoproteins and cell surfaces. We also seek to determine how such recognition leads to targeting of biological functions and how genetic variation in sugar-binding receptors causes changes in their molecular properties and hence contributes to human disease. Of particular interest are sugar-binding receptors found on cells of the immune system such as macrophages and dendritic cells. In addition to biochemical studies, we are using techniques of cell biology to determine how these receptors traffic within cells to mediate phagocytosis or endocytosis of micro-organisms or foreign proteins. These studies aim to give insight into how sugar-binding receptors are involved in infection of cells with micro-organisms causing diseases such as AIDS, SARS, tuberculosis and leprosy.

研究领域

My research interest is in structure-function analysis of proteins, particularly of carbohydrate-recognition proteins involved in the innate immune response against pathogens and in glycoprotein homeostasis. The work has focussed on understanding molecular mechanisms involved in selective recognition of glycoproteins and cell surface carbohydrates and the biological functions mediated by carbohydrate recognition. Molecular characterization of the mannose receptor My early career focussed on two proteins, the mannose receptor and serum mannose-binding protein. The mannose receptor of liver endothelial cells and macrophages clears proteins such as lysosomal enzymes that bear high mannose oligosaccharides and are released during pathological events and plays a role in innate immunity against micro-organisms. As a graduate student I studied the cell biology and kinetics of clearance of glycoproteins by the hepatic mannose receptor and characterized soluble mannose-binding proteins from human serum. I cloned and sequenced the gene for the major human serum mannose-binding protein, which mediates complement-dependent killing of micro-organisms. Later, I cloned the cDNA for the human mannose receptor and found it to have an unusual multidomain structure including eight C-type carbohydrate-recognition domains. This arrangement of domains has since been found in three other endocytic receptors, making the mannose receptor the prototype for a family of multi-domain receptors. Subsequently I characterized the roles of the various domains of the receptor with the goal of gaining a molecular understanding of how the receptor binds and internalizes pathogens and harmful glycoproteins. Using a combination of biochemical, biophysical, cell and molecular biological approaches, we showed that several of the C-type carbohydrate-recognition domains are involved in binding and internalization of mannose-terminated glycoconjugates. We characterized the mechanism of calcium and sugar binding by the receptor, determined the crystal structure of the principle ligand-binding carbohydrate-recognition domain, in collaboration with Bill Weis at Stanford, and determined a mechanism by which the receptor can release its ligands in the endosomes. We showed that the mannose receptor has an additional function in binding of collagen through the fibronectin type II domain. We helped apply methods developed in studying the mannose receptor to other members of the "mannose receptor family", such as Endo-180. We have provided cDNA clones and cell lines expressing the mannose receptor to many groups world-wide to facilitate their studies on biological functions of the mannose receptor. Molecular characterization of other C-type lectins C-type lectins identified from genome sequence data are now the subject of much of our work. Examples include langerin, a receptor specific to Langerhans cells, and the scavenger receptor C-type lectin of endothelial cells. For langerin, we determined oligomeric structure, ligand-binding specificity, demonstrated the ability to mediate endocytosis of glycoproteins and recently solved the crystal structure of the trimeric extracellular region of the receptor, showing the disposition of the ligand-binding sites. We have shown that amino-acid changes due to polymorphisms in the langerin gene affect stability and ligand-binding by langerin, a finding that is important in understanding susceptibility to infectious organisms, such as HIV, that interact with langerin. For the scavenger receptor C-type lectin, in addition to biochemical characterization of the protein we have demonstrated high specificity for binding to the Lewis-X trisaccharide and determined the mechanism of this interaction by solving the crystal structure of the carbohydrate-recognition domain in complex with Lewis-X. The specificity of this receptor for a single endogenous oligosaccharide suggests a role in cell adhesion or clearance of specific glycoproteins. We have also contributed to molecular characterization of several other proteins involved in binding of viruses and other pathogens including the dendritic cell receptor DC-SIGN and the endothelial cell receptors DC-SIGNR and LSECtin and have recently identified new C-type lectins in the human genome. Communication to a wider audience To make the field of glycobiology accessible to undergraduates, I co-authored the first textbook in this area. Introduction to Glycobiology is now going into its 3rd edition and has been translated into Japanese, Chinese and Korean.

近期论文

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Feinberg H, Rambaruth ND, Jégouzo SA, Jacobsen KM, Djurhuus R, Poulsen TB, Weis WI, Taylor ME, Drickamer Ket al., 2016, Binding Sites for Acylated Trehalose Analogs of Glycolipid Ligands on an Extended Carbohydrate Recognition Domain of the Macrophage Receptor Mincle., J Biol Chem, Vol: 291, Pages: 21222-21233 Drickamer K, Taylor ME, 2015, Recent insights into structures and functions of C-type lectins in the immune system, CURRENT OPINION IN STRUCTURAL BIOLOGY, Vol: 34, Pages: 26-34, ISSN: 0959-440X Jegouzo SAF, Feinberg H, Dungarwalla T, Drickamer K, Weis WI, Taylor MEet al., 2015, A Novel Mechanism for Binding of Galactose-terminated Glycans by the C-type Carbohydrate Recognition Domain in Blood Dendritic Cell Antigen 2, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 290, Pages: 16759-16771, ISSN: 0021-9258 Rambaruth NDS, Jegouzo SAF, Marlor H, Taylor ME, Drickamer Ket al., 2015, Mouse Mincle: Characterization as a Model for Human Mincle and Evolutionary Implications, MOLECULES, Vol: 20, Pages: 6670-6682, ISSN: 1420-3049 Jegouzo SAF, Harding EC, Acton O, Rex MJ, Fadden AJ, Taylor ME, Drickamer Ket al., 2014, Defining the conformation of human mincle that interacts with mycobacterial trehalose dimycolate, GLYCOBIOLOGY, Vol: 24, Pages: 1291-1300, ISSN: 0959-6658 Taylor ME, Drickamer K, 2014, Convergent and divergent mechanisms of sugar recognition across kingdoms, CURRENT OPINION IN STRUCTURAL BIOLOGY, Vol: 28, Pages: 14-22, ISSN: 0959-440X Feinberg H, Jegouzo SAF, Rowntree TJW, Guan Y, Brash MA, Taylor ME, Weis WI, Drickamer Ket al., 2013, Mechanism for Recognition of an Unusual Mycobacterial Glycolipid by the Macrophage Receptor Mincle, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 288, Pages: 28457-28465, ISSN: 0021-9258 Feinberg H, Rowntree TJW, Tan SLW, Drickamer K, Weis WI, Taylor MEet al., 2013, Common Polymorphisms in Human Langerin Change Specificity for Glycan Ligands, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 288, Pages: 36762-36771, ISSN: 0021-9258 Jegouzo SAF, Quintero-Martinez A, Ouyang X, dos Santos A, Taylor ME, Drickamer Ket al., 2013, Organization of the extracellular portion of the macrophage galactose receptor: A trimeric cluster of simple binding sites for N-acetylgalactosamine, GLYCOBIOLOGY, Vol: 23, Pages: 853-864, ISSN: 0959-6658 Feinberg H, Taylor ME, Razi N, McBride R, Knirel YA, Graham SA, Drickamer K, Weis WIet al., 2011, Structural Basis for Langerin Recognition of Diverse Pathogen and Mammalian Glycans through a Single Binding Site, JOURNAL OF MOLECULAR BIOLOGY, Vol: 405, Pages: 1027-1039, ISSN: 0022-2836 Graham SA, Antonopoulos A, Hitchen PG, Haslam SM, Dell A, Drickamer K, Taylor MEet al., 2011, Identification of Neutrophil Granule Glycoproteins as Lewis(x)-containing Ligands Cleared by the Scavenger Receptor C-type Lectin, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 286, Pages: 24336-24349, ISSN: 0021-9258 Leckband DE, Menon S, Rosenberg K, Graham SA, Taylor ME, Drickamer Ket al., 2011, Geometry and Adhesion of Extracellular Domains of DC-SIGNR Neck Length Variants Analyzed by Force-Distance Measurements, BIOCHEMISTRY, Vol: 50, Pages: 6125-6132, ISSN: 0006-2960 Pipirou Z, Powlesland AS, Steffen I, Poehlmann S, Taylor ME, Drickamer Ket al., 2011, Mouse LSECtin as a model for a human Ebola virus receptor, GLYCOBIOLOGY, Vol: 21, Pages: 806-812, ISSN: 0959-6658 Powlesland AS, Marcela Barrio M, Mordoh J, Hitchen PG, Dell A, Drickamer K, Taylor MEet al., 2011, Glycoproteomic characterization of carriers of the CD15/Lewis(x) epitope on Hodgkin's Reed-Sternberg cells, BMC BIOCHEMISTRY, Vol: 12, ISSN: 1471-2091 Taylor ME, Drickamer K, 2011, Introduction to Glycobiology, Third Edition, Publisher: Oxford University Press, ISBN: 978-0-19-956911-3 Coombs PJ, Harrison R, Pemberton S, Quintero-Martinez A, Parry S, Haslam SM, Dell A, Taylor ME, Drickamer Ket al., 2010, Identification of Novel Contributions to High-affinity Glycoprotein-Receptor Interactions using Engineered Ligands, JOURNAL OF MOLECULAR BIOLOGY, Vol: 396, Pages: 685-696, ISSN: 0022-2836 Feinberg H, Powlesland AS, Taylor ME, Weis WIet al., 2010, Trimeric Structure of Langerin, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 285, Pages: 13285-13293, ISSN: 0021-9258 Powlesland AS, Quintero-Martinez A, Lim PG, Pipirou Z, Taylor ME, Drickamer Ket al., 2010, ENGINEERED CARBOHYDRATE-RECOGNITION DOMAINS FOR GLYCOPROTEOMIC ANALYSIS OF CELL SURFACE GLYCOSYLATION AND LIGANDS FOR GLYCAN-BINDING RECEPTORS, METHODS IN ENZYMOLOGY, VOL 480: GLYCOBIOLOGY, Vol: 480, Pages: 165-179, ISSN: 0076-6879 de Jong MAWP, Vriend LEM, Theelen B, Taylor ME, Fluitsma D, Boekhout T, Geijtenbeek TBHet al., 2010, C-type lectin Langerin is a beta-glucan receptor on human Langerhans cells that recognizes opportunistic and pathogenic fungi, MOLECULAR IMMUNOLOGY, Vol: 47, Pages: 1216-1225, ISSN: 0161-5890 de Jong MAWP, de Witte L, Santegoets SJAM, Fluitsma D, Taylor ME, de Gruijl TD, Geijtenbeek TBHet al., 2010, Mutz-3-derived Langerhans cells are a model to study HIV-1 transmission and potential inhibitors, JOURNAL OF LEUKOCYTE BIOLOGY, Vol: 87, Pages: 637-643, ISSN: 0741-5400

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