Recently, prof. George Fu Gao’s group described the molecular mechanism of KSHV gHgL and EBV gHgL binding to EphA2 receptor. The article entitled “Molecular basis of EphA2 recognition by gHgL from gammaherpesviruses” was published in Nature Communications on November 24, 2020.
The human γ-herpesviruses Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) are associated with many human malignancies. Viral glycoprotein H (gH) and glycoprotein L (gL) are crucial for the cell tropism by binding to specific receptors. Recently, EphA2 was identified as the specific entry receptor for both KSHV and EBV. However, it is still unclear for the molecular mechanism of EphA2 recognition by gHgL.
They characterized the crystal structures of KSHV gHgL or EBV gHgL in complex with the ligand binding domain (LBD) of EphA2. Both KSHV and EBV gHgL bind to the channel and peripheral regions of LBD primarily using gL. Extensive interactions with more contacts contribute to the higher affinity of KSHV gHgL to LBD than that of EBV gHgL. These binding characteristics were verified using cell-based fusion assays with mutations in key EphA2 residues.
Fig.1 Complex structure of KSHV or EBV gHgL bound to EphA2 LBD.
Fig.2 EphA2 might serve as an entry receptor for multiple γ-herpesviruses.
They further found multiple animal γ-herpesviruses could use EphA2 as an entry receptor, implying the potential threats to human health. Thus, their work revealed the structural basis of EphA2 recognition by γ-herpesvirus gHgL, and help to clarify the entry mechanisms of KSHV and EBV, which may inform the development of specific drugs to target the γ-herpesvirus entry process.
Dr. Chao Su and Lili Wu are the first co-authors and prof. George Fu Gao, Jinghua Yan and Hao Song are the corresponding authors. This work was supported by the National Natural Science Foundation of China, the Strategic Priority Research Program of the Chinese Academy of Sciences (CAS), National Science and Technology Major Project and the Youth Innovation Promotion Association of CAS.