Viral entry mechanisms

Structural Basis for Receptor Recognition by Lujo Virus

Cohen-Dvashi H., et al., Nat. Micro., 2018

Lujo virus (LUJV) is a highly fatal Arenavirus that does not classify with the known Old and New World groups of that viral family. To provide the basis for combating LUJV, we used X-ray crystallography to reveal how the GP1 receptor-binding domain of LUJV (LUJVGP1) recognizes its primary receptor neuropilin-2 (NRP2). Structural data shows that LUJVGP1 is more similar to OW than to NW arenaviruses. Structural analysis suggests that NRP2 recognition is metal ion (Ca+2) dependent and that the complete NRP2 binding site is formed in the context of the trimeric spike.

Structural Basis for Receptor Selectivity by the Whitewater Arroyo Mammarenavirus

Shimon A., et al., JMB,2017

We solved the first crystal structure of a receptor-binding domain of the non-pathogenic mammarenavirus, Whitewater Arroyo. This structure reveals the magnitude of structural differences within the receptor-binding domains of TfR1-tropic viruses. Our structural and sequence analyses indicate that the same structural incompatibilities with the human receptor equally affect both pathogenic and non-pathogenic mammarenaviruses. Non-pathogenic viruses do not have specific structural elements that prevent them from using the human receptor. Instead, the ability to utilize the human receptor directly depends on the extent of weak interactions throughout the receptor-binding site that in some viruses are sufficiently strong to overcome the structural incompatibilities

Mapping of the Lassa Virus LAMP1 Binding Site Reveals Unique Determinants Not Shared by Other Old World Arenaviruses

 

Israeli H., et al., PLoS Path., 2017

We solved the crystal structure of the GP1 receptor-binding domain from Morogoro virus, which is genetically close to Lassa virus. This GP1 cannot bind LAMP1 like the GP1 from Lassa virus. Using comparative analysis we mapped the LAMP1 binding site. The site that we have identified is necessary and sufficient for binding to LAMP1 as indicated by grafting experiments.

 

The role of LAMP1 binding and pH sensing by the spike complex of Lassa virus (LASV)

Cohen-Dvashi H. et al., JVI, 2016

To effectively infect cells, Lassa virus needs to switch in endosomal compartment from its primary receptor a-dystroglycan to LAMP1. We found in LASV`s GP1 structure a unique histidine triad important for LAMP1 binding. We mutated the histidins and spikes had impaired ability to interact with LAMP1. Our studies reveal an important regulatory role for histidines from the triad in sensing acidic pH and preventing premature spike triggering. We further showed that LAMP1 requires a positively charged His230 to engage with the spike complex and that LAMP1 binding promotes membrane fusion.

Atomic Structure of the LASV receptor-binding domain

Cohen-Dvashi H., et al., JVI, 2015

The surface glycoprotein of Lassa virus (LASV) mediates receptor recognition through its GP1 subunit. We solved the crystal structure of GP1 from LASV and identified a unique triad of histidines that forms a binding site for LAMP1, a known lysosomal protein which is a critical receptor for internalized Lassa virus at acidic pH. Our biochemical and structural data suggest that GP1 from Lassa undergoes irreversible conformational changes that could serve as an immunological decoy mechanism.