7ul7 | pdb_00007ul7
Lineage I (Pinneo) Lassa virus glycoprotein bound to 18.5C-M30 Fab
Structural highlights
Function[Q9IMJ0_LASV] Glycoprotein G1: interacts with the host receptor.[HAMAP-Rule:MF_04084] Glycoprotein G2: 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 upon acidification in the endosome.[HAMAP-Rule:MF_04084] Stable signal peptide (SSP): cleaved and functions as a signal peptide. In addition, it is also retained as the third component of the GP complex. The SSP is required for efficient glycoprotein expression, post-translational maturation cleavage of GP1 and GP2, 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. References
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