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Flavivirus maturation leads to the formation of an occupied lipid pocket in the surface glycoproteins

DOI: 10.1038/s41467-021-21505-9 DOI Help

Authors: Max Renner (The Wellcome Centre for Human Genetics, University of Oxford) , Wanwisa Dejnirattisai (The Wellcome Centre for Human Genetics, University of Oxford) , Loic Carrique (The Wellcome Centre for Human Genetics, University of Oxford) , Itziar Serna Martin (Utrecht University) , Dimple Karia (The Wellcome Centre for Human Genetics, University of Oxford) , Serban L. Ilca (The Wellcome Centre for Human Genetics, University of Oxford) , Shu F. Ho (The Wellcome Centre for Human Genetics, University of Oxford) , Abhay Kotecha (The Wellcome Centre for Human Genetics, University of Oxford) , Jeremy R. Keown (The Wellcome Centre for Human Genetics, University of Oxford) , Juthathip Mongkolsapaya (The Wellcome Centre for Human Genetics, University of Oxford; Mahidol University) , Gavin R. Screaton (The Wellcome Centre for Human Genetics, University of Oxford) , Jonathan M. Grimes (The Wellcome Centre for Human Genetics, University of Oxford; Diamond Light Source)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 12

State: Published (Approved)
Published: February 2021
Diamond Proposal Number(s): 20223

Open Access Open Access

Abstract: Flaviviruses such as Dengue (DENV) or Zika virus (ZIKV) assemble into an immature form within the endoplasmatic reticulum (ER), and are then processed by furin protease in the trans-Golgi. To better grasp maturation, we carry out cryo-EM reconstructions of immature Spondweni virus (SPOV), a human flavivirus of the same serogroup as ZIKV. By employing asymmetric localised reconstruction we push the resolution to 3.8 Å, enabling us to refine an atomic model which includes the crucial furin protease recognition site and a conserved Histidine pH-sensor. For direct comparison, we also solve structures of the mature forms of SPONV and DENV to 2.6 Å and 3.1 Å, respectively. We identify an ordered lipid that is present in only the mature forms of ZIKV, SPOV, and DENV and can bind as a consequence of rearranging amphipathic stem-helices of E during maturation. We propose a structural role for the pocket and suggest it stabilizes mature E.

Journal Keywords: Dengue virus; Electron microscopy

Diamond Keywords: Dengue Fever; Viruses

Subject Areas: Biology and Bio-materials

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios IV-Titan Krios IV at Diamond

Documents:
s41467-021-21505-9.pdf

Discipline Tags:

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

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)