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Molecular changes in dengue envelope protein domain III upon interaction with glycosaminoglycans

DOI: 10.3390/pathogens9110935 DOI Help

Authors: James G. Hyatt (Keele University) , Sylvain Prévost (Institut Laue-Langevin) , Juliette M. Devos (Institut Laue-Langevin) , Courtney J. Mycroft-West (Keele University) , Mark A. Skidmore (Keele University) , Anja Winter (Keele University; Institut Laue-Langevin)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Pathogens , VOL 9

State: Published (Approved)
Published: November 2020
Diamond Proposal Number(s): 25074

Open Access Open Access

Abstract: Dengue fever is a rapidly emerging vector-borne viral disease with a growing global burden of approximately 390 million new infections per annum. The Dengue virus (DENV) is a flavivirus spread by female mosquitos of the aedes genus, but the mechanism of viral endocytosis is poorly understood at a molecular level, preventing the development of effective transmission blocking vaccines (TBVs). Recently, glycosaminoglycans (GAGs) have been identified as playing a role during initial viral attachment through interaction with the third domain of the viral envelope protein (EDIII). Here, we report a systematic study investigating the effect of a range of biologically relevant GAGs on the structure and oligomeric state of recombinantly generated EDIII. We provide novel in situ biophysical evidence that heparin and chondroitin sulphate C induce conformational changes in EDIII at the secondary structure level. Furthermore, we report the ability of chondroitin sulphate C to bind EDIII and induce higher-order dynamic molecular changes at the tertiary and quaternary structure levels which are dependent on pH, GAG species, and the GAG sulphation state. Lastly, we conducted ab initio modelling of Small Angle Neutron Scattering (SANS) data to visualise the induced oligomeric state of EDIII caused by interaction with chondroitin sulphate C, which may aid in TBV development.

Journal Keywords: dengue virus; envelope protein; glycosaminoglycans; protein-glycosaminoglycan interactions; small-angle scattering

Diamond Keywords: Dengue Fever; Viruses

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: B21-High Throughput SAXS

Other Facilities: BM29 at ESRF

Added On: 19/11/2020 08:35

Discipline Tags:

Vaccines Pathogens Infectious Diseases Disease in the Developing World Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)