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April 5th, 2025
Version: 1
Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
biochemistry
biorxiv

Human endogenous retrovirus K (HERV-K) envelope structures in pre- and post-fusion by Cryo-EM

Shek, J.Open in Google Scholar•Sun, C.Open in Google Scholar•Wilson, E. M.Open in Google Scholar•Moadab, F.Open in Google Scholar•Hastie, K. M.Open in Google Scholar•Rajamanickam, R. R.Open in Google Scholar•Penalosa, P. J.Open in Google Scholar•Harkins, S. S.Open in Google Scholar•Parakh, D.Open in Google Scholar•Hariharan, C.Open in Google Scholaret al.

The HERV-K envelope glycoprotein (Env) is aberrantly expressed in diseases including cancers and autoimmune disorders and is targeted by antibodies. The lack of structural information has hindered functional and immune recognition studies. We solved structures of the HERV-K Env in both pre- and post-fusion states with novel monoclonal antibodies using cryo-EM. The pre-fusion Env assembles as a trimer with a distinct fold and architecture compared to other retroviruses, while the post-fusion conformation features a unique tether helix within the TM subunit. A panel of monoclonal antibodies, elicited to facilitate structure determination, have been characterized for conformational and subunit specificity, serving as valuable research tools. These findings establish a structural framework for mechanistic studies of HERV-K Env in diseases and evaluation as a potential therapeutic target.

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