Structure and receptor recognition by the Lassa virus spike complex

Michael Katz, Jonathan Weinstein, Maayan Eilon-Ashkenazy, Katrin Gehring, Hadas Cohen-Dvashi, Nadav Elad, Sarel J. Fleishman and Ron Diskin ()
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Michael Katz: Weizmann Institute of Science
Jonathan Weinstein: Weizmann Institute of Science
Maayan Eilon-Ashkenazy: Weizmann Institute of Science
Katrin Gehring: Weizmann Institute of Science
Hadas Cohen-Dvashi: Weizmann Institute of Science
Nadav Elad: Weizmann Institute of Science
Sarel J. Fleishman: Weizmann Institute of Science
Ron Diskin: Weizmann Institute of Science

Nature, 2022, vol. 603, issue 7899, 174-179

Abstract: Abstract Lassa virus (LASV) is a human pathogen, causing substantial morbidity and mortality1,2. Similar to other Arenaviridae, it presents a class-I spike complex on its surface that facilitates cell entry. The virus’s cellular receptor is matriglycan, a linear carbohydrate that is present on α-dystroglycan3,4, but the molecular mechanism that LASV uses to recognize this glycan is unknown. In addition, LASV and other arenaviruses have a unique signal peptide that forms an integral and functionally important part of the mature spike5–8; yet the structure, function and topology of the signal peptide in the membrane remain uncertain9–11. Here we solve the structure of a complete native LASV spike complex, finding that the signal peptide crosses the membrane once and that its amino terminus is located in the extracellular region. Together with a double-sided domain-switching mechanism, the signal peptide helps to stabilize the spike complex in its native conformation. This structure reveals that the LASV spike complex is preloaded with matriglycan, suggesting the mechanism of binding and rationalizing receptor recognition by α-dystroglycan-tropic arenaviruses. This discovery further informs us about the mechanism of viral egress and may facilitate the rational design of novel therapeutics that exploit this binding site.

Date: 2022
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DOI: 10.1038/s41586-022-04429-2

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