In situ insights into antibody-mediated neutralization of a pre-fusion Junin virus glycoprotein complex
Lily J. Taylor,
Michael R. Sawaya,
Jonna B. Westover,
Chenyi Wang,
Frederick Jimenez,
Aldo J. Muñoz,
Julian Whitelegge,
Brian B. Gowen,
Gustavo F. Helguera,
Roger Castells-Graells,
Jose A. Rodriguez
Affiliations
Lily J. Taylor
Department of Chemistry and Biochemistry, UCLA-DOE Institute for Genomics and Proteomics, STROBE, NSF Science and Technology Center, University of California, California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Corresponding author
Michael R. Sawaya
Department of Chemistry and Biochemistry, UCLA-DOE Institute for Genomics and Proteomics, STROBE, NSF Science and Technology Center, University of California, California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
Jonna B. Westover
Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT 84322, USA
Chenyi Wang
The Pasarow Mass Spectrometry Laboratory, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, California (UCLA), Los Angeles, CA, USA
Frederick Jimenez
Department of Chemistry and Biochemistry, UCLA-DOE Institute for Genomics and Proteomics, STROBE, NSF Science and Technology Center, University of California, California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
Aldo J. Muñoz
Department of Chemistry and Biochemistry, UCLA-DOE Institute for Genomics and Proteomics, STROBE, NSF Science and Technology Center, University of California, California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
Julian Whitelegge
The Pasarow Mass Spectrometry Laboratory, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, California (UCLA), Los Angeles, CA, USA
Brian B. Gowen
Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT 84322, USA; Corresponding author
Gustavo F. Helguera
Laboratory of Pharmaceutical Biotechnology, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina; Corresponding author
Roger Castells-Graells
Department of Chemistry and Biochemistry, UCLA-DOE Institute for Genomics and Proteomics, STROBE, NSF Science and Technology Center, University of California, California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Corresponding author
Jose A. Rodriguez
Department of Chemistry and Biochemistry, UCLA-DOE Institute for Genomics and Proteomics, STROBE, NSF Science and Technology Center, University of California, California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Corresponding author
Summary: A transmembrane glycoprotein complex (GPC) decorates the Junin mammarenavirus (JUNV) that causes New World hemorrhagic fevers. We leveraged single-particle cryoelectron microscopy (cryo-EM) to image the full-length JUNV GPC directly on pseudotyped virus (PV) membranes and bound by two JUNV-neutralizing antibodies: Candid#1 vaccine-elicited CR1-28 and J199, a potent therapeutic against Argentine hemorrhagic fever (AHF). The 3.8 Å resolution in situ structures of the antibody-neutralized, 3-fold symmetric JUNV GPC reveal its ectodomain architecture, signal peptide-bound transmembrane region, zinc-binding luminal domain, and post-translational modifications. JUNV-GPC sequence variants highlight the functional importance of the signal peptide transmembrane helix register for virus infection and attenuating Candid#1-associated variants. Overlapping CR1-28 and J199 epitopes suggest a common receptor-blocking mechanism for JUNV neutralization, while a J199-induced, symmetric GPC reorientation may further drive its potent inhibition of JUNV lethality in mice, compared to receptor blockade alone. This underscores the utility of in situ insights into GPC function and neutralization.
