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Hashiguchi Takao Last modified date:2019.06.20

Associate Professor / Department of Pathological Sciences
Department of Basic Medicine
Faculty of Medical Sciences

Academic Degree
Ph. D
Field of Specialization
virology, structural biology
Outline Activities
Research for the viral pathogenesis and vaccine development by structural biology.
Education for the undergrad and grad students about virology.
Research Interests
  • Structural analysis for the viral pathogenesis and vaccine development.
    keyword : virus, receptor, vaccine, antibody, structural biology, x-ray crystallographic analysis
Academic Activities
1. Hashiguchi Takao, Maenaka Katsumi, Yusuke Yanagi, Measles virus hemagglutinin: structural insights into cell entry and measles vaccine., Front Microbiol., 2011.12.
2. Yusuke Yanagi, Makoto Takeda, Ohno Shinji, Hashiguchi Takao, Measles virus receptors., Curr Top Microbiol Immunol., 2009.01.
1. Takao Hashiguchi, Yoshinari Fukuda, Rei Matsuoka, Daisuke Kuroda, Marie Kubota, Yuta Shirogane, Shumpei Watanabe, Kouhei Tsumoto, Daisuke Kohda, Richard Karl Plemper, Yusuke Yanagi, Structures of the prefusion form of measles virus fusion protein in complex with inhibitors, Proceedings of the National Academy of Sciences of the United States of America, 10.1073/pnas.1718957115, 115, 10, 2496-2501, 2018.03, Measles virus (MeV), a major cause of childhood morbidity and mortality, is highly immunotropic and one of the most contagious pathogens. MeV may establish, albeit rarely, persistent infection in the central nervous system, causing fatal and intractable neurodegenerative diseases such as subacute sclerosing panencephalitis and measles inclusion body encephalitis. Recent studies have suggested that particular substitutions in the MeV fusion (F) protein are involved in the pathogenesis by destabilizing the F protein and endowing it with hyperfusogenicity. Here we show the crystal structures of the prefusion MeV-F alone and in complex with the small compound AS-48 or a fusion inhibitor peptide. Notably, these independently developed inhibitors bind the same hydrophobic pocket located at the region connecting the head and stalk of MeV-F, where a number of substitutions in MeV isolates from neurodegenerative diseases are also localized. Since these inhibitors could suppress membrane fusion mediated by most of the hyperfusogenic MeV-F mutants, the development of more effective inhibitors based on the structures may be warranted to treat MeV-induced neurodegenerative diseases..
2. Marie Kubota, Kaoru Takeuchi, Shumpei Watanabe, Shinji Ohno, Rei Matsuoka, Daisuke Kohda, Shin Ichi Nakakita, Hiroaki Hiramatsu, Yasuo Suzuki, Tetsuo Nakayama, Tohru Terada, Kentaro Shimizu, Nobutaka Shimizu, Mitsunori Shiroishi, Yusuke Yanagi, Takao Hashiguchi, Trisaccharide containing α2,3-linked sialic acid is a receptor for mumps virus, Proceedings of the National Academy of Sciences of the United States of America, 10.1073/pnas.1608383113, 113, 41, 11579-11584, 2016.10, Mumps virus (MuV) remains an important pathogen worldwide, causing epidemic parotitis, orchitis, meningitis, and encephalitis. Here we show that MuV preferentially uses a trisaccharide containing α2,3-linked sialic acid in unbranched sugar chains as a receptor. Crystal structures of the MuV attachment protein hemagglutinin-neuraminidase (MuV-HN) alone and in complex with the α2,3-sialylated trisaccharide revealed that in addition to the interaction between the MuV-HN active site residues and sialic acid, other residues, including an aromatic residue, stabilize the third sugar of the trisaccharide. The importance of the aromatic residue and the third sugar in the MuV-HN-receptor interaction was confirmed by computational energy calculations, isothermal titration calorimetry studies, and glycan-binding assays. Furthermore, MuV-HN was found to bind more efficiently to unbranched α2,3-sialylated sugar chains compared with branched ones. Importantly, the strategically located aromatic residue is conserved among the HN proteins of sialic acid-using paramyxoviruses, and alanine substitution compromised their ability to support cell-cell fusion. These results suggest that not only the terminal sialic acid but also the adjacent sugar moiety contribute to receptor function for mumps and these paramyxoviruses. The distribution of structurally different sialylated glycans in tissues and organs may explain in part MuV's distinct tropism to glandular tissues and the central nervous system. In the crystal structure, the epitopes for neutralizing antibodies are located around the α-helices of MuV-HN that are not well conserved in amino acid sequences among different genotypes of MuV. This may explain the fact that MuV reinfection sometimes occurs..
3. Marnie L. Fusco, Hashiguchi Takao, Robyn Cassan, Julia E. Biggins, Charles D. Murin, Kelly L. Warfield, Sheng Li, Frederick W. Holtsberg, Sergey Shulenin, Hong Vu, Gene G. Olinger, Do H. Kim, Kevin J. Whaley, Larry Zeitlin, Andrew B. Ward, Cory Nykiforuk, M. Javad Aman, Jody D. Berry, Erica Ollmann Saphire, Protective mAbs and Cross-Reactive mAbs Raised by Immunization with Engineered Marburg Virus GPs, PLoS Pathogens, 10.1371/journal.ppat.1005016, 11, 6, e1005016, 2015.06.
4. Andrew I. Flyak, Philipp A. Ilinykh, Charles D. Murin, Tania Garron, Xiaoli Shen, Marnie L. Fusco, Takao Hashiguchi, Zachary A. Bornholdt, James C. Slaughter, Gopal Sapparapu, Curtis Klages, Thomas G. Ksiazek, Andrew B. Ward, Erica Ollmann Saphire, Alexander Bukreyev, James E. Crowe, Mechanism of Human Antibody-Mediated Neutralization of Marburg Virus, Cell, 10.1016/j.cell.2015.01.031, 160, 5, 893-903, 2015.02.
5. Takao Hashiguchi, Marnie L. Fusco, Zachary A. Bornholdt, Jeffrey E. Lee, Andrew I. Flyak, Rei Matsuoka, Daisuke Kohda, Yusuke Yanagi, Michal Hammel, James E. Crowe, Erica Ollmann Saphire, Structural Basis for Marburg Virus Neutralization by a Cross-Reactive Human Antibody, Cell, 10.1016/j.cell.2015.01.041, 160, 5, 904-912, 2015.02, The filoviruses, including Marburg and Ebola, express a single glycoprotein on their surface, termed GP, which is responsible for attachment and entry of target cells. Filovirus GPs differ by up to 70% in protein sequence, and no antibodies are yet described that cross-react among them. Here, we present the 3.6 Å crystal structure of Marburg virus GP in complex with a cross-reactive antibody from a human survivor, and a lower resolution structure of the antibody bound to Ebola virus GP. The antibody, MR78, recognizes a GP1 epitope conserved across the filovirus family, which likely represents the binding site of their NPC1 receptor. Indeed, MR78 blocks binding of the essential NPC1 domain C. These structures and additional small-angle X-ray scattering of mucin-containing MARV and EBOV GPs suggest why such antibodies were not previously elicited in studies of Ebola virus, and provide critical templates for development of immunotherapeutics and inhibitors of entry..
6. Takao Hashiguchi, Toyoyuki Ose, Marie Kubota, Nobuo Maita, Jun Kamishikiryo, Katsumi Maenaka, Yusuke Yanagi, Structure of the measles virus hemagglutinin bound to its cellular receptor SLAM, Nature Structural and Molecular Biology, 10.1038/nsmb.1969, 18, 2, 135-142, 2011.02, Measles virus, a major cause of childhood morbidity and mortality worldwide, predominantly infects immune cells using signaling lymphocyte activation molecule (SLAM) as a cellular receptor. Here we present crystal structures of measles virus hemagglutinin (MV-H), the receptor-binding glycoprotein, in complex with SLAM. The MV-H head domain binds to a β-sheet of the membrane-distal ectodomain of SLAM using the side of its β-propeller fold. This is distinct from attachment proteins of other paramyxoviruses that bind receptors using the top of their β-propeller. The structure provides templates for antiviral drug design, an explanation for the effectiveness of the measles virus vaccine, and a model of the homophilic SLAM-SLAM interaction involved in immune modulations. Notably, the crystal structures obtained show two forms of the MV-H-SLAM tetrameric assembly (dimer of dimers), which may have implications for the mechanism of fusion triggering..
7. Takao Hashiguchi, Mizuho Kajikawa, Nobuo Maita, Makoto Takeda, Kimiko Kuroki, Kaori Tabata, Daisuke Kohda, Yusuke Yanagi, Katsumi Maenaka, Crystal structure of measles virus hemagglutinin provides insight into effective vaccines, Proceedings of the National Academy of Sciences of the United States of America, 10.1073/pnas.0707830104, 104, 49, 19535-19540, 2007.12, Measles still remains a major cause of childhood morbidity and mortality worldwide. Measles virus (MV) vaccines are highly successful, but the mechanism underlying their efficacy has been unclear. Here we report the crystal structure of the MV attachment protein, hemagglutinin, responsible for MV entry. The receptor-binding head domain exhibits a cubic-shaped β-propeller structure and forms a homodimer. N-linked sugars appear to mask the broad regions and cause the two molecules forming the dimer to tilt oppositely toward the horizontal plane. Accordingly, residues of the putative receptor-binding site, highly conserved among MV strains, are strategically positioned in the unshielded area of the protein. These conserved residues also serve as epitopes for neutralizing antibodies, ensuring the serological monotype, a basis for effective MV vaccines. Our findings suggest that sugar moieties in the MV hemagglutinin critically modulate virus-receptor interaction as well as antiviral antibody responses, differently from sugars of the HIV gp120, which allow for immune evasion..
1. Hashiguchi T, Measles virus-mediated membrane fusion linked with CNS disorders: Structural basis for its inhibition by inhibitors and hyperfusogenicity caused by mutations, Membrane fusion in health and disease, 2018.06.
2. Takao Hashiguchi, Molecular dissection of virus entry and its inhibition by antibodies/inhibitors, The 9th International Symposium of IFReC, 2018.01.
3. Hashiguchi, T, Molecular basis for Mononegavirus entry and inhibitions by antibodies/inhibitors, The 16th Awaji International Forum on Infection and Immunity (AIFII 16), 2017.09.
4. Hashiguchi Takao, Inhibitory mechanisms of anti-filovirus antibodies on Marburg and Ebola virus entry, Institute for Protein Research (IPR) International Seminar IPR / CRED / PDIS Joint Seminar, 2016.01.
5. Hashiguchi Takao, Structural basis for filovirus neutralization by antibodies, The 63rd Annual meeting of the Japanese Society for Virology, 2015.11.
6. Hashiguchi Takao, Nakashima Mai, Shirogane Yuta, Maenaka Katsumi, Yusuke Yanagi, Structures of measles virus hemagglutinin provide virus entry and effective measles vaccine, The 12th Awaji International Forum on Infection and Immunity , 2013.09, [URL].
7. Hashiguchi Takao, Kubota Marie, Nakashima Mai, Shirogane Yuta, Ose Toyoyuki, Maenaka Katsumi, Yusuke Yanagi, Structural and functional insight into measles virus hemagglutinin, 7th International Conference on Structural Genomics (ICSG2013-SLS), 2013.07.
8. Hashiguchi Takao, Makoto Takeda, Maenaka Katsumi, Yusuke Yanagi, Crystal structure of the measles virus hemagglutinin sheds light on its interaction with cellular receptors and antibodies, 27th Annual Meeting of American Scociety for Virology., 2008.07.
Membership in Academic Society
  • The Japanese Society for Virology
Educational Activities
Structural basis for pathogenesis and vaccine of viral infectious disease.