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bioRxiv · 10.1101/2025.03.19.644160

The prefusion structure of the HERV-K (HML-2) Env spike complex

Shaked, R.·Katz, M.·Cohen-Dvashi, H.·Diskin, R.
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Abstract

The human endogenous retrovirus K (HERV-K) is a retrovirus that got assimilated into the human genome in ancient times and has been inherited in our germline ever since. It enters cells using a class-I spike protein (Env) that mediates receptor recognition and membrane fusion. On top of having a biological role during development, HERV-K is activated in amyotrophic lateral sclerosis, various cancers, and other pathological conditions. Antibodies that target the HERV-K spike complex have therapeutic value, flagging the spike as a novel drug target. Here, we use cryo-EM to determine the trimeric structure of the HERV-K spike. The spike presents a distinct structure, which substantially differs from other class-I fusogens. Nevertheless, some general architectural features suggest a common origin with other retroviruses. Our structural analysis points to the putative receptor binding sites of the spike and provides insights into its function. The ability to structurally characterize the HERV-K spike may facilitate the development of antibody-based therapies. SignificanceRetroviruses integrate their genomes into host cell DNA. When this occurs in germline cells, the retroviral elements can be inherited and become part of the offspring genome. HERV-K is one such retrovirus that integrated into the human genome in ancient times. Over time, it gained a role in embryonic development but is also linked to various diseases, making it a potential drug target. To enter cells, HERV-K uses a spike protein, whose atomic structure we determined using electron microscopy. This structure reveals insights into the spikes function and HERV-Ks evolutionary ties with contemporary viruses. This structural information further provides a foundation for future drug development.

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Shaked, R., Katz, M., Cohen-Dvashi, H., Diskin, R.. 2025-03-19. The prefusion structure of the HERV-K (HML-2) Env spike complex. https://doi.org/10.1101/2025.03.19.644160

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