7uds
Structure of lineage I (Pinneo) Lassa virus glycoprotein bound to Fab 25.10C
Structural highlights
FunctionQ9IMJ0_LASV Forms the virion spikes together with glycoprotein G2. The glycoprotein spike trimers are connected to the underlying matrix. Interacts with the host receptor. Mediates virus attachment to the host primary receptor alpha-dystroglycan DAG1 (alpha-DG) at the cell surface. This attachment induces virion internalization apparently through macropinocytosis. Following endocytosis, there is a pH-dependent switch from binding DAG1 to the host lysosomal receptor LAMP1. This latter binding triggers the dissociation of GP1, exposing the fusion subunit, GP2, such that fusion can occur. Down-modulates host DAG1.[HAMAP-Rule:MF_04084] Forms the virion spikes together with glycoprotein G1. The glycoprotein spike trimers are connected to the underlying matrix. Class I viral fusion protein that directs fusion of viral and host endosomal membranes, leading to delivery of the nucleocapsid into the cytoplasm. Membrane fusion is mediated by irreversible conformational changes induced by acidification.[HAMAP-Rule:MF_04084] Functions as a cleaved signal peptide that is retained as the third component of the GP complex (GP-C). Helps to stabilize the spike complex in its native conformation. The SSP is required for efficient glycoprotein expression, post-translational maturation cleavage of G1 and G2, glycoprotein transport to the cell surface plasma membrane, formation of infectious virus particles, and acid pH-dependent glycoprotein-mediated cell fusion.[HAMAP-Rule:MF_04084] Publication Abstract from PubMedLassa virus (LASV) is the causative agent of the deadly Lassa fever (LF). Seven distinct LASV lineages circulate through western Africa, among which lineage I (LI), the first to be identified, is particularly resistant to antibody neutralization. Lineage I LASV evades neutralization by half of known antibodies in the GPC-A antibody competition group and all but one of the antibodies in the GPC-B competition group. Here, we solve two cryo-electron microscopy (cryo-EM) structures of LI GP in complex with a GPC-A and a GPC-B antibody. We used complementary structural and biochemical techniques to identify single-amino-acid substitutions in LI that are responsible for immune evasion by each antibody group. Further, we show that LI infection is more dependent on the endosomal receptor lysosome-associated membrane protein 1 (LAMP1) for viral entry relative to LIV. In the absence of LAMP1, LI requires a more acidic fusion pH to initiate membrane fusion with the host cell relative to LIV. IMPORTANCE No vaccine or therapeutics are approved to prevent LASV infection or treat LF. All vaccine platforms currently under development present only the LIV GP sequence. However, our data suggest that the high genetic diversity of LASV may be problematic for designing both a broadly reactive immunogen and therapeutic. Here, we examine antibodies that are highly potent against LIV yet are ineffective against LI. By pinpointing LI mutations responsible for this decrease in antibody efficacy, we suggest that future vaccine platforms may need to incorporate specific LI-like mutations in order to generate a broadly neutralizing antibody response against all LASV lineages. Neutralizing Antibodies against Lassa Virus Lineage I.,Buck TK, Enriquez AS, Schendel SL, Zandonatti MA, Harkins SS, Li H, Moon-Walker A, Robinson JE, Branco LM, Garry RF, Saphire EO, Hastie KM mBio. 2022 Aug 30;13(4):e0127822. doi: 10.1128/mbio.01278-22. Epub 2022 Jun 22. PMID:35730904[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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