PMID- 25144748 OWN - NLM STAT- MEDLINE DCOM- 20151221 LR - 20211021 IS - 1553-7374 (Electronic) IS - 1553-7366 (Print) IS - 1553-7366 (Linking) VI - 10 IP - 8 DP - 2014 Aug TI - Assembly and architecture of the EBV B cell entry triggering complex. PG - e1004309 LID - 10.1371/journal.ppat.1004309 [doi] LID - e1004309 AB - 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. FAU - Sathiyamoorthy, Karthik AU - Sathiyamoorthy K AD - Department of Structural Biology, Stanford University School of Medicine, Stanford, California, United States of America. FAU - Jiang, Jiansen AU - Jiang J AD - Department of Microbiology, Immunology & Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America; California NanoSystems Institute, University of California Los Angeles, Los Angeles, California, United States of America. FAU - Hu, Yao Xiong AU - Hu YX AD - Department of Structural Biology, Stanford University School of Medicine, Stanford, California, United States of America. FAU - Rowe, Cynthia L AU - Rowe CL AD - Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America. FAU - Mohl, Britta S AU - Mohl BS AD - Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America. FAU - Chen, Jia AU - Chen J AD - Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America. FAU - Jiang, Wei AU - Jiang W AD - Department of Pediatrics, Program in Immunology, Stanford University School of Medicine, Stanford, California, United States of America. FAU - Mellins, Elizabeth D AU - Mellins ED AD - Department of Pediatrics, Program in Immunology, Stanford University School of Medicine, Stanford, California, United States of America. FAU - Longnecker, Richard AU - Longnecker R AD - Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America. FAU - Zhou, Z Hong AU - Zhou ZH AD - Department of Microbiology, Immunology & Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America; California NanoSystems Institute, University of California Los Angeles, Los Angeles, California, United States of America. FAU - Jardetzky, Theodore S AU - Jardetzky TS AD - Department of Structural Biology, Stanford University School of Medicine, Stanford, California, United States of America. LA - eng GR - R01 CA133063/CA/NCI NIH HHS/United States GR - CA117794/CA/NCI NIH HHS/United States GR - R21 AI095813/AI/NIAID NIH HHS/United States GR - UL1 RR025744/RR/NCRR NIH HHS/United States GR - UL1 TR001085/TR/NCATS NIH HHS/United States GR - AI069015/AI/NIAID NIH HHS/United States GR - R01 AI076183/AI/NIAID NIH HHS/United States GR - CA133063/CA/NCI NIH HHS/United States GR - AI076183/AI/NIAID NIH HHS/United States GR - R01 CA117794/CA/NCI NIH HHS/United States GR - AI095813/AI/NIAID NIH HHS/United States GR - R01 AI069015/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20140821 PL - United States TA - PLoS Pathog JT - PLoS pathogens JID - 101238921 RN - 0 (HLA-DQ Antigens) RN - 0 (HLA-DQ2 antigen) RN - 0 (Membrane Glycoproteins) RN - 0 (Molecular Chaperones) RN - 0 (Viral Envelope Proteins) RN - 0 (Viral Proteins) RN - 0 (glycoprotein H, Herpesvirus 4) RN - 0 (glycoprotein L, Human herpesvirus 4) SB - IM MH - Animals MH - B-Lymphocytes/*virology MH - CHO Cells MH - Cricetinae MH - Cricetulus MH - Epstein-Barr Virus Infections/*metabolism MH - HLA-DQ Antigens/metabolism MH - Herpesvirus 4, Human/*pathogenicity MH - Host-Parasite Interactions/*physiology MH - Image Processing, Computer-Assisted MH - Membrane Glycoproteins/metabolism MH - Microscopy, Electron MH - Molecular Chaperones/metabolism MH - Viral Envelope Proteins/metabolism MH - Viral Proteins/metabolism MH - *Virus Internalization PMC - PMC4140853 COIS- The authors have declared that no competing interests exist. EDAT- 2014/08/22 06:00 MHDA- 2015/12/22 06:00 PMCR- 2014/08/21 CRDT- 2014/08/22 06:00 PHST- 2014/02/19 00:00 [received] PHST- 2014/07/01 00:00 [accepted] PHST- 2014/08/22 06:00 [entrez] PHST- 2014/08/22 06:00 [pubmed] PHST- 2015/12/22 06:00 [medline] PHST- 2014/08/21 00:00 [pmc-release] AID - PPATHOGENS-D-14-00440 [pii] AID - 10.1371/journal.ppat.1004309 [doi] PST - epublish SO - PLoS Pathog. 2014 Aug 21;10(8):e1004309. doi: 10.1371/journal.ppat.1004309. eCollection 2014 Aug.