biostudies-literatureZaigraev MMRussian Science Foundation11https://www.ebi.ac.uk/biostudies/studies/S-EPMC9819746biostudies-literatureUnknown24(1)Ly6/uPAR proteins regulate many essential functions in the nervous and immune systems and epithelium. Most of these proteins contain single β-structural LU domains with three protruding loops and are glycosylphosphatidylinositol (GPI)-anchored to a membrane. The GPI-anchor role is currently poorly studied. Here, we investigated the positional and orientational preferences of six GPI-anchored proteins in the receptor-unbound state by molecular dynamics simulations. Regardless of the linker length between the LU domain and GPI-anchor, the proteins interacted with the membrane by polypeptide parts and N-/O-glycans. Lynx1, Lynx2, Lypd6B, and Ly6H contacted the membrane by the loop regions responsible for interactions with nicotinic acetylcholine receptors, while Lypd6 and CD59 demonstrated uniInternational journal of molecular sciencesOrientational Preferences of GPI-Anchored Ly6/uPAR Proteins.PMC981974619-74-20176Paramonov ASChugunov AOLyukmanova ENZaigraev MMShenkarev ZOfalseOrientational Preferences of GPI-Anchored Ly6/uPAR Proteins.Ly6/uPAR proteins regulate many essential functions in the nervous and immune systems and epithelium. Most of these proteins contain single β-structural LU domains with three protruding loops and are glycosylphosphatidylinositol (GPI)-anchored to a membrane. The GPI-anchor role is currently poorly studied. Here, we investigated the positional and orientational preferences of six GPI-anchored proteins in the receptor-unbound state by molecular dynamics simulations. Regardless of the linker length between the LU domain and GPI-anchor, the proteins interacted with the membrane by polypeptide parts and N-/O-glycans. Lynx1, Lynx2, Lypd6B, and Ly6H contacted the membrane by the loop regions responsible for interactions with nicotinic acetylcholine receptors, while Lypd6 and CD59 demonstrated uni2022-01-01T00:00:00Z2022 Dec2025-04-21T16:20:49.415Z2025-04-21T16:20:49.415ZS-EPMC98197463661345610.3390/ijms24010011