8t5c
Lassa GPC Trimer in complex with Fab 8.11G and nanobody D5
Structural highlights
FunctionGLYC_LASSJ Stable signal peptide (SSP) is cleaved but is apparently retained as the third component of the GP complex. The SSP is required for efficient glycoprotein expression, post-translational cleavage of GP1 and GP2, glycoprotein transport to the cell plasma membrane, formation of infectious virus particles, and acid pH-dependent glycoprotein-mediated cell fusion. The GP complex interacts with host glycosylated LAMP1 to mediate efficient infection.[1] Glycoprotein G1 mediates virus attachment to host receptor alpha-dystroglycan DAG1. This attachment induces virion internalization predominantly through clathrin- and caveolin-independent endocytosis. Glycoprotein G2 is a 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 irreversable conformational changes induced upon acidification in the endosome (By similarity). Publication Abstract from PubMedLassa virus (LASV) infection is expanding outside its traditionally endemic areas in West Africa, posing a pandemic biothreat. LASV-neutralizing antibodies, moreover, have proven difficult to elicit. To gain insight into LASV neutralization, here we develop a prefusion-stabilized LASV glycoprotein trimer (GPC), pan it against phage libraries comprising single-domain antibodies (nanobodies) from shark and camel, and identify one, D5, which neutralizes LASV. Cryo-EM analyses reveal D5 to recognize a cleavage-dependent site-of-vulnerability at the trimer apex. The recognized site appears specific to GPC intermediates, with protomers lacking full cleavage between GP1 and GP2 subunits. Guinea pig immunizations with the prefusion-stabilized cleavage-intermediate LASV GPC, first as trimer and then as a nanoparticle, induce neutralizing responses, targeting multiple epitopes including that of D5; we identify a neutralizing antibody (GP23) from the immunized guinea pigs. Collectively, our findings define a prefusion-stabilized GPC trimer, reveal an apex-situated site-of-vulnerability, and demonstrate elicitation of LASV-neutralizing responses by a cleavage-intermediate LASV trimer. Cleavage-intermediate Lassa virus trimer elicits neutralizing responses, identifies neutralizing nanobodies, and reveals an apex-situated site-of-vulnerability.,Gorman J, Cheung CS, Duan Z, Ou L, Wang M, Chen X, Cheng C, Biju A, Sun Y, Wang P, Yang Y, Zhang B, Boyington JC, Bylund T, Charaf S, Chen SJ, Du H, Henry AR, Liu T, Sarfo EK, Schramm CA, Shen CH, Stephens T, Teng IT, Todd JP, Tsybovsky Y, Verardi R, Wang D, Wang S, Wang Z, Zheng CY, Zhou T, Douek DC, Mascola JR, Ho DD, Ho M, Kwong PD Nat Commun. 2024 Jan 4;15(1):285. doi: 10.1038/s41467-023-44534-y. PMID:38177144[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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