Structural Insights into Endogenous Retroviruses: Evolution and Co-Opted Functions

Abstract

Endogenous retroviruses (ERVs) are the molecular remnants of ancient retroviral infections and constitute a substantial fraction of many vertebrate genomes. Although most ERV loci have lost coding capacity and are epigenetically silenced, some remain biologically relevant because they have been co-opted for host physiology. Recent advances in structural biology are beginning to clarify how these elements have evolved from infectious retroviruses into genomic components with diverse molecular and cellular functions. In this review, we organise current structural insights by retroviral functional modules: group-specific antigen (Gag), polymerase (Pol) and envelope (Env). In the Gag section, we describe capsid-related assemblies of human endogenous retrovirus K (HERV-K), including mature-like CA assemblies reconstituted in vitro and immature lattices resolved in intact virus-like particles, as well as structural studies of the endogenous lentiviruses RELIK and PSIV. In the Pol section, we discuss HERV-K reverse transcriptase, biochemical studies of protease, and emerging structural evidence for integrase. In the Env section, we review prefusion and postfusion structures of HERV-K Env and receptor-bound structures of domesticated Env proteins, including syncytin-1, syncytin-2 and suppressyn. Together, these studies show how structural approaches can connect ERV evolution with molecular function, while also defining major unresolved questions regarding conformational dynamics, host interactions, and physiological relevance.