biostudies-literatureHong YNational Science Foundation (NSF)National Science Foundation8411https://www.ebi.ac.uk/biostudies/studies/S-EPMC12462473biostudies-literatureUnknown16(1)Lipid-anchored proteins are integral components of cell surfaces. In bacteria, lipidation of proteins with a conserved lipobox motif ([L/V/I]^-3 [A/S/T/V/I]^-2 [G/A/S]^-1 [C]⁺¹) is catalyzed by prolipoprotein diacylglyceryl transferase (Lgt). Although lipobox-containing proteins, or lipoproteins, are predicted to be abundant in several archaeal species, no archaeal homologs of Lgt have been identified, suggesting distinct lipidation enzymes evolved in archaea to accommodate their unique membrane lipids. Here, we predicted lipoprotein presence for all major archaeal lineages and revealed a high prevalence of lipoproteins across the domain Archaea. Using comparative genomics, we identified a comprehensive set of candidates for archaeal lipoprotein bioNature communicationsUncovering the prevalence, key biogenesis enzymes, and biological significance of archaeal lipoproteins.PMC12462473EAR-1752564MBC-2222076Makarova KSHong YXu RWelander PVPohlschroder MGarcia AAPfeiffer FfalseUncovering the prevalence, key biogenesis enzymes, and biological significance of archaeal lipoproteins.Lipid-anchored proteins are integral components of cell surfaces. In bacteria, lipidation of proteins with a conserved lipobox motif ([L/V/I]^-3 [A/S/T/V/I]^-2 [G/A/S]^-1 [C]⁺¹) is catalyzed by prolipoprotein diacylglyceryl transferase (Lgt). Although lipobox-containing proteins, or lipoproteins, are predicted to be abundant in several archaeal species, no archaeal homologs of Lgt have been identified, suggesting distinct lipidation enzymes evolved in archaea to accommodate their unique membrane lipids. Here, we predicted lipoprotein presence for all major archaeal lineages and revealed a high prevalence of lipoproteins across the domain Archaea. Using comparative genomics, we identified a comprehensive set of candidates for archaeal lipoprotein bio2025-01-01T00:00:00Z2025 Sep2026-06-03T21:13:04.092Z2026-05-01T03:10:37.429ZS-EPMC124624734099883910.1038/s41467-025-63625-6