The lipid raft markers stomatin, prohibitin, flotillin, and HflK/C (SPFH)-domain proteins form an operon with NfeD proteins and function with apolar polyisoprenoid lipids.

SPFH-domain proteins are found in almost all organisms across three domains: archaea, bacteria, and eukaryotes. In eukaryotic organelles, their subfamilies exhibit overlapping distribution and functions; thus, the rationality of annotation to discriminate these subfamilies remains unclear. In this review, the binding ability of prokaryotic SPFH-domain proteins towards nonpolar polyisoprenoides such as squalene and lycopene, rather than cholesterol, is discussed. The hydrophobic region at the C-terminus of SPFH-domain proteins constitutes the main region that binds apolar polyisoprenoid lipids as well as cholesterol and substantively contributes towards lipid raft formation as these regions are self-assembled together with specific lipids. Because the scaffolding proteins caveolins show common topological properties with SPFH-domain proteins such as stomatin and flotillin, the alpha-helical segments of stomatin proteins can flexibly move along with the membrane surface, with such movement potentially leading to membrane bending via lipid raft clustering through the formation of high order homo-oligomeric complexes of SPFH-domain proteins. We also discuss the functional significance and ancient origin of SPFH-domain proteins and the NfeD protein (STOPP) operon, which can be traced back to the ancient living cells that diverged and evolved to archaea and bacteria. Based on the molecular mechanism whereby the STOPP-protease degrades the C-terminal hydrophobic clusters of SPFH-domain proteins, it is conceivable that STOPP-protease might control the physicochemical properties of lipid rafts.