Crystal structure of HERV-K envelope glycoprotein surface subunit
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The most recently acquired and transcriptionally active family of human endogenous retroviruses (HERVs) is HERV-K. Of the approximately 100 copies of HERV-K in our genome, many retain the potential to proliferate by retrotransposition, express viral proteins, and form functional virus particles. Aberrant expression of the HERV-K envelope glycoprotein (Env) has been associated with cancer and neurodegeneration. Autoantibodies against HERV-K Env have been found in patients with various autoimmune diseases. Here, we report the crystal structures of the Env surface subunit (SU) from HERV-K HML-2, determined at 2.25 Å resolution. The overall fold is somewhat similar to Syncycin-2 SU and distantly related to HIV-1 gp120. The structure contains five disulfide bonds and four N-linked glycans, including one glycan that appears important for structural stability. Two extended loops form a surface for potential interactions with cell-surface receptors or other cellular factors. The structure also contains three detergent molecules, similar in structure to cholesterol, bound to hydrophobic surface patches. This crystal structure provides a platform for future studies to map autoantigenic epitopes, identify small-molecules that interfere with HERV-K activity, and extend our mechanistic understanding of retroviruses.
IMPORTANCE
15% of the human genome consists of endogenous retroviruses and other virus-derived elements inherited from ancestral viral infections. Many endogenous retroviruses from the HERV-K family retain the ability to proliferate across the genome and produce virus-like particles. Aberrant expression of the HERV-K envelope glycoprotein is associated with cancer, neurodegeneration, and autoimmune disease. Here, we report the crystal structure of the HERV-K envelope glycoprotein surface subunit. The structure provides a view in atomic-level detail of the molecular components in HERV-K most likely to trigger autoimmune responses. The structure also identifies binding sites for drug-like molecules, paving the way for future studies to develop new therapeutics.
