heptad repeat 1-heptad repeat 2 region of the transmembrane subunit of various endogenous retroviruses (ERVs) and infectious retroviruses, including Ebola virus and Rous sarcoma virus
This domain family spans both heptad repeats of the glycoprotein (gp)/transmembrane subunit of endogenous retroviruses (ERVs) and infectious retroviruses, including Ebola virus gp2, Rous sarcoma virus gp37, and the envelope proteins of various ERVs. This domain includes an N-terminal heptad repeat, a CKS17-like immunosuppressive region, a CX6C motif that forms an intra-subunit disulfide bond, and a C-terminal heptad repeat. N-terminal to HR1-HR2 region is a fusion peptide (FP), while C-terminal, is a membrane-spanning region (MSR). Viral infection involves the formation of a trimer-of-hairpins structure (three HR1s helices, buttressed by three HR2 helices lying in antiparallel orientation). In this structure, the FP (inserted in the host cell membrane) and MSR (inserted in the viral membrane) are in close proximity. ERVs are likely to originate from ancient germ-line infections by active retroviruses. Some modern ERVs, those that integrated into the host genome post-speciation, have a currently active exogenous counterpart, such as Jaagsiekte sheep retrovirus (JSRV), feline leukemia virus (FeLV), and avian leukemia virus (ALV). Some ERVs play specific roles in the host, including placental development, protection of the host from infection by related pathogenic and exogenous retroviruses, and genome plasticity. Human ERVs (HERVs) belonging to this family include Syncytin-1 (HERV-W_c7q21.2/ ERVWE1), and Syncytin-2 (HERV-FRD_6p24.1) which are expressed in the placenta, and are fusogenic, although they have a different cell specificity for fusion. Syncytin-2, but not Syncytin-1, is immunosuppressive. Its immunosuppressive domain may protect the fetus from the mother's immune system. Syncytin-1 may participate in the formation of the placental trophoblast. It is also implicated in cell fusions between cancer and host cells and between cancer cells, and in human osteclast fusion. This family also contains human HERV-R_c7q21.2 (ERV-3), which is also expressed in the placenta, but is not fusogenic, has an immunosuppressive domain, but lacks a fusion peptide. It is unclear whether ERV-3 has a critical biological role.
Comment: The conformation of Ebola virus HR1 changes significantly in the pre-fusion (three-helix bundle) and post-fusion (six-helix bundle) conformations of the HR1-HR2 region.
Jiyao W et al.(2023). "The conserved domain database in 2023.",