학술논문
The structure of a C. neoformans polysaccharide motif recognized by protective antibodies: A combined NMR and MD study.
Document Type
Academic Journal
Author
Hargett AA; Laboratory of Bacterial Polysaccharides, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993.; Azurmendi HF; Laboratory of Bacterial Polysaccharides, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993.; Crawford CJ; W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205.; Centre for Synthesis and Chemical Biology, University College Dublin, Dublin 4, Ireland.; Wear MP; W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205.; Oscarson S; Centre for Synthesis and Chemical Biology, University College Dublin, Dublin 4, Ireland.; Casadevall A; W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205.; Freedberg DI; Laboratory of Bacterial Polysaccharides, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993.
Source
Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
Subject
Language
English
Abstract
Cryptococcus neoformans is a fungal pathogen responsible for cryptococcosis and cryptococcal meningitis. The C. neoformans ' capsular polysaccharide and its shed exopolysaccharide function both as key virulence factors and to protect the fungal cell from phagocytosis. Currently, a glycoconjugate of these polysaccharides is being explored as a vaccine to protect against C. neoformans infection. In this study, NOE and J -coupling values from NMR experiments were consistent with a converged structure of the synthetic decasaccharide, GXM10-Ac 3 , calculated from MD simulations. GXM10-Ac 3 was designed as an extension of glucuronoxylomannan (GXM) polysaccharide motif (M2) which is common in the clinically predominant serotype A strains and is recognized by protective forms of GXM-specific monoclonal antibodies. The M2 motif is a hexasaccharide with a three-residue α-mannan backbone, modified by β-(1→2)-xyloses (Xyl) on the first two mannoses (Man) and a β-(1→2)-glucuronic acid (GlcA) on the third Man. Combined NMR and MD analyses reveal that GXM10-Ac 3 adopts an extended structure, with Xyl/GlcA branches alternating sides along the α-mannan backbone. O -acetyl esters also alternate sides and are grouped in pairs. MD analysis of a twelve M2-repeating unit polymer supports the notion that the GXM10-Ac 3 structure is uniformly represented throughout the polysaccharide. This derived GXM model displays high flexibility while maintaining a structural identity, yielding insights to further explore intermolecular interactions between polysaccharides, interactions with anti-GXM mAbs, and the cryptococcal polysaccharide architecture.
Competing Interests: Competing interests statement:The authors declare no competing interest.
Competing Interests: Competing interests statement:The authors declare no competing interest.