FXYDs are small single-transmembrane proteins that act as novel regulators of Na+/K+-ATPase (NKA). The transmembrane domain and the conserved Phe-X-Tyr-Asp motif of FXYD play a role in the binding of FXYD to the alpha- and beta-subunits of NKA. PFXYD (proline-phenylalanine-X-tyrosine-aspartate) at the beginning of the signature sequence is invariant in all known examples in mammals and identical except for the proline in other vertebrates; X is usually Y (tyrosine), but can also be E, T, or H (glutamate, threonine, or histidine). The FXYD protein family contains at least twelve members that have the extracellular FXYD motif, transmembrane domain, and intracellular domain. Members share a 35-amino acid signature sequence domain, beginning with PFXYD and containing 7 invariant and 6 highly conserved amino acids. In mammals, members of the FXYD family include FXYD1 (phospholemman, PLM), FXYD2 (the gamma-subunit of NKA), FXYD3 (mammary tumor marker Mat-8), FXYD4 (corticosteroid hormone-induced factor, CHIF), FXYD5 (dysadherin), FXYD6 (phosphohippolin), and FXYD7. In elasmobranchs, FXYD10 (phospholemman-like protein from shark, PLMS) was first identified in the rectal glands of Squalus acanthias. In addition, studies on sharks reported that the functions of FXYD10 via its C-terminal cysteine residue interactions were associated with negative regulation of shark NKA activity. Teleostean FXYD proteins (FXYD2, 5-9, 11, and 12) have been reported in certain teleosts such as the Tetraodon nigroviridis, Salmo salar, Danio rerio, and Oryzias dancena. Recent studies have demonstrated that several teleost FXYD isoforms are expressed in the gills and kidneys of the fish, and their expression levels are altered in response to salinity changes, suggesting that these FXYDs may regulate electrolyte homeostasis and body fluid of the fish.
Structure:2ZXE: Squalus acanthias Na(+)/K(+)-ATPase regulatory FXYD protein (phospholemman-like protein) forms a heterotrimer with the alpha and beta subunits; contacts at 4A
Jiyao W et al.(2023). "The conserved domain database in 2023.",