Assembly and Architecture of the EBV B Cell Entry Triggering Complex

Karthik Sathiyamoorthy, Jiansen Jiang, Yao Xiong Hu, Cynthia L. Rowe, Britta S. Möhl, Jia Chen, Wei Jiang, Elizabeth D. Mellins, Richard Longnecker, Z. Hong Zhou, Theodore S. Jardetzky*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

Epstein-Barr Virus (EBV) is an enveloped double-stranded DNA virus of the gammaherpesvirinae sub-family that predominantly infects humans through epithelial cells and B cells. Three EBV glycoproteins, gH, gL and gp42, form a complex that targets EBV infection of B cells. Human leukocyte antigen (HLA) class II molecules expressed on B cells serve as the receptor for gp42, triggering membrane fusion and virus entry. The mechanistic role of gHgL in herpesvirus entry has been largely unresolved, but it is thought to regulate the activation of the virally-encoded gB protein, which acts as the primary fusogen. Here we study the assembly and function of the reconstituted B cell entry complex comprised of gHgL, gp42 and HLA class II. The structure from negative-stain electron microscopy provides a detailed snapshot of an intermediate state in EBV entry and highlights the potential for the triggering complex to bring the two membrane bilayers into proximity. Furthermore, gHgL interacts with a previously identified, functionally important hydrophobic pocket on gp42, defining the overall architecture of the complex and playing a critical role in membrane fusion activation. We propose a macroscopic model of the initiating events in EBV B cell fusion centered on the formation of the triggering complex in the context of both viral and host membranes. This model suggests how the triggering complex may bridge the two membrane bilayers, orienting critical regions of the N- and C- terminal ends of gHgL to promote the activation of gB and efficient membrane fusion.

Original languageEnglish (US)
Article numbere1004309
JournalPLoS pathogens
Volume10
Issue number8
DOIs
StatePublished - Aug 21 2014

Funding

Funding: This research was supported by NIH (http://www.nih.gov/) grants AI076183 (RL and TSJ), AI095813 (EDM) and AI069015 (ZHZ) from National Institute of Allergy and Infectious Diseases, and by CA117794 (RL and TSJ) and CA133063 (RL and CLR) from the National Cancer Institute. WJ was supported by the Stanford NIH/NCRR CTSA award (UL1 RR025744) and the Lucile Packard Foundation for Children’s Health (http://www.lpfch.org/). JC was supported by a postdoctoral fellowship 12POST9380013 and 14POST18600021 from American Heart Association, Midwest Affiliate. BSM was supported by a postdoctoral scholarship from the Deutsche Forschungsgemeinschaft (MO 2500/1-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This research was supported by NIH (http://www.nih.gov/) grants AI076183 (RL and TSJ), AI095813 (EDM) and AI069015 (ZHZ) from National Institute of Allergy and Infectious Diseases, and by CA117794 (RL and TSJ) and CA133063 (RL and CLR) from the National Cancer Institute. WJ was supported by the Stanford NIH/NCRR CTSA award (UL1 RR025744) and the Lucile Packard Foundation for Children?s Health (http://www.lpfch.org/). JC was supported by a postdoctoral fellowship 12POST9380013 and 14POST18600021 from American Heart Association, Midwest Affiliate. BSM was supported by a postdoctoral scholarship from the Deutsche Forschungsgemeinschaft (MO 2500/1-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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