Taxonomic group: fungi / Basidiomycota
(Phylum: Basidiomycota)
Organ / tissue: capsuleAssociated disease: infection due to Cryptococcus neoformans [ICD11:
XN3EH 
]
NCBI PubMed ID: 32517333Publication DOI: 10.3390/molecules25112651Journal NLM ID: 100964009Publisher: Basel, Switzerland: MDPI
Correspondence: Kuttel MM <mkuttel
cs.uct.ac.za>; Casadevall A <acasade1
jhu.edu>; Oscarson S <stefan.oscarson
ucd.ie>
Institutions: Department of Computer Science, University of Cape Town, Cape Town, South Africa, Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, USA, Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Ireland
The pathogenic encapsulated Cryptococcus neoformans fungus causes serious disease in immunosuppressed hosts. The capsule, a key virulence factor, consists primarily of the glucuronoxylomannan polysaccharide (GXM) that varies in composition according to serotype. While GXM is a potential vaccine target, vaccine development has been confounded by the existence of epitopes that elicit non-protective antibodies. Although there is evidence for protective antibodies binding conformational epitopes, the secondary structure of GXM remains an unsolved problem. Here an array of molecular dynamics simulations reveal that the GXM mannan backbone is consistently extended and relatively inflexible in both C. neoformans serotypes A and D. Backbone substitution does not alter the secondary structure, but rather adds structural motifs: β-D-GlcA and β-D-Xyl side chains decorate the mannan backbone in two hydrophillic fringes, with mannose-6-O-acetylation forming a hydrophobic ridge between them. This work provides mechanistic rationales for clinical observations-the importance of O-acetylation for antibody binding; the lack of binding of protective antibodies to short GXM fragments; the existence of epitopes that elicit non-protective antibodies; and the self-aggregation of GXM chains-indicating that molecular modelling can play a role in the rational design of conjugate vaccines.
molecular modelling, conformation, epitope, capsular polysaccharide, conjugate vaccines, carbohydrate antigen, Cryptococcus neoformans, GXM
Structure type: suggested polymer biological repeating unit
Location inside paper: Fig. 1, A
Trivial name: glucuronoxylomannan (GXM)
Compound class: CPS, EPS, O-polysaccharide, O-antigen, cell wall polysaccharide, polysaccharide, glucuronoxylomannan, capsule polysaccharide
Contained glycoepitopes: IEDB_114701,IEDB_115136,IEDB_115576,IEDB_130701,IEDB_140116,IEDB_140630,IEDB_144983,IEDB_145668,IEDB_152206,IEDB_164174,IEDB_167188,IEDB_174332,IEDB_2270799,IEDB_423153,IEDB_76933,IEDB_983930,SB_197,SB_44,SB_67,SB_72
Methods: molecular modeling, molecular dynamics
Related record ID(s): 50860
NCBI Taxonomy refs (TaxIDs): 178876Reference(s) to other database(s): GTC:G75580HK, CCSD:
50376, CBank-STR:15059
Show glycosyltransferases
There is only one chemically distinct structure:
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(later renamed to: Cryptococcus neoformans var. grubii)