phenylalanine-X-tyrosine-aspartate (FXYD) family; 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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 258679518  2 ELVLVFLCSLLAPMVLASAAEKEKEMDPFHYDYQTLRIGGLVFAVVLFSVGILLILSRRCKCSFNQKPRAPGDEEAQVEN 81
Cdd:cd20327   1 EVVLIFVCSLLIPVVLASAAKKEKEIDPFHYNYQTLRIGGLVFDMVLFLVLSLHLLSHRCKCSFNQKPQDPGDEEAQVEN 80

                        90
                ....*....|...
gi 258679518 82 LITANATEPQKAE 94
Cdd:cd20327  81 FITANAKEPQKAK 93

FXYD domain-containing ion transport regulator 8; FXYD domain-containing ion transport regulator 8 (FXYD8), also known as FXYD domain containing ion transport regulator 6 pseudogene 3 (FXYD6P3), is a member of the FXYD protein family that is involved in the modulation of NKA activity in the kidneys. The human FXYD8 gene is located on the X chromosome. However, the gene is located on chromosome 9 in the mouse and chromosome 8 in the rat.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 258679518  2 ELVLVFLCSLLAPMVLASAAEKEKEMDPFHYDYQTLRIGGLVFAVVLFSVGILLILSRRCKCSFNQKPRAPGDEEAQVEN 81
Cdd:cd20327   1 EVVLIFVCSLLIPVVLASAAKKEKEIDPFHYNYQTLRIGGLVFDMVLFLVLSLHLLSHRCKCSFNQKPQDPGDEEAQVEN 80

                        90
                ....*....|...
gi 258679518 82 LITANATEPQKAE 94
Cdd:cd20327  81 FITANAKEPQKAK 93

FXYD domain-containing ion transport regulator 8; FXYD domain-containing ion transport regulator 8 (FXYD8), also known as FXYD domain containing ion transport regulator 6 pseudogene 3 (FXYD6P3), is a member of the FXYD protein family that is involved in the modulation of NKA activity in the kidneys. The human FXYD8 gene is located on the X chromosome. However, the gene is located on chromosome 9 in the mouse and chromosome 8 in the rat.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 258679518  2 ELVLVFLCSLLAPMVLASAAEKEKEMDPFHYDYQTLRIGGLVFAVVLFSVGILLILSRRCKCSFNQKPRAPGDEEAQVEN 81
Cdd:cd20327   1 EVVLIFVCSLLIPVVLASAAKKEKEIDPFHYNYQTLRIGGLVFDMVLFLVLSLHLLSHRCKCSFNQKPQDPGDEEAQVEN 80

                        90
                ....*....|...
gi 258679518 82 LITANATEPQKAE 94
Cdd:cd20327  81 FITANAKEPQKAK 93

ATP1G1/PLM/MAT8 family;

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*...
gi 258679518  25 KEMDPFHYDYQTLRIGGLVFAVVLFSVGILLILSRRCKCSFNQKPRAP 72
Cdd:pfam02038  1 DEDDPFYYDYETLRIGGLIFAGLLFIVGILIILSKKCKCKFNQKPRSP 48

FXYD domain-containing ion transport regulator 3 and similar proteins; This subfamily includes FXYD domain-containing ion transport regulator 3 (FXYD3), FXYD9, and FXYD10, also called PLMS/Phospholemman-like protein. FXYD3, also known as mammary tumor 8 kDa protein (MAT-8), or chloride conductance inducer protein Mat-8, or phospholemman-like (PLML), may function as a chloride channel or as a chloride channel regulator. It associates with and regulates the activity of the sodium/potassium-transporting ATPase (NKA) which transports Na+ out of the cell and K+ into the cell. Two transcript variants encode two different isoforms of the protein; in addition, transcripts utilizing alternative polyA signals have been described in the literature. Members here include mammalians and reptiles. FXYD9 is present in teleosts including: Danio rerio, Atlantic salmon, and Japanese Medaka fish. In general, the FXYD9 isoform has the highest degree of conservation among the examined teleost species, indicating that it may be involved in physiological processes that are not evolving within this group of vertebrates. FXYD10, present in shark, associates with and modifies the activity of Na,K-ATPase in vitro through interactions mediated by its transmembrane and cytoplasmic C-terminal domains. It is important in the phosphorylation and potassium deocclusion reactions, which are known to be controlled by A domain movements. It is thought that FXYD10 interacts with the A domain of the shark Na,K-ATPase alpha-subunit.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 258679518 20 AAEKEKEMDPFHYDYQTLRIGGLVFAVVLFSVGILLILSRRCKCSFNQKPR 70
Cdd:cd20328   1 ANDPEDKDSPFYYDWHRLRVGGLICAAVLCAIGIIVLLSGKCKCKFNQKKR 51

FXYD domain-containing ion transport regulator 7; FXYD domain-containing ion transport regulator 7 (FXYD7) has a potential splice variant with an additional 3 residues. In rats, expression of FXYD7 was restricted to the brain, with highest levels in the cerebrum, followed by brainstem, and hippocampus, and relatively weak expression in the hypothalamus. Immunofluorescence microscopy demonstrated colocalization with synaptophysin and modest colocalization with glial fibrillary acidic protein, indicating predominant expression in neurons and lower expression in astroglial cells. The FXYD7 gene maps to chromosome 19.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 258679518 26 EMDPFHYDYQTLRIGGLVFAVVLFSVGILLILSRRCKCSFNQKPRAP 72
Cdd:cd20325   3 DQSPFEYDYETLRTTGVILAVVMFVLGILIALSKKFKCKKSDSSKSL 49

FXYD domain of FXYD domain-containing ion transport regulator 5; FXYD domain-containing ion transport regulator 5 (FXYD5) is also called dysadherin in humans or related to ion channel (RIC) in mice. Two transcript variants have been found for this gene, and they are both predicted to encode the same protein. Dysadherin is the gamma subunit the human Na,K-ATPase and is the only member that has a large extracellular sequence of 140 amino acids. Dysadherin has been observed to be over-expressed on the surface of cells that have down regulated levels of surface E-cadherin. CCL2 (bone homing cytokine) is a protein that is highly affected by silencing dysadherin expression. Dysadherin interferes with cell adhesion via beta1 subunit interactions and is a target for an extracellular antibody drug conjugate where the antibody to dysadherin is attached to a cardiac glycoside. FXYD5 expression in mouse is mainly in the kidney, intestine, spleen, and lung. Confocal immunofluorescence microscopy of mouse kidney detected FXYD5 on basolateral membranes of connecting tubules, collecting tubules, intercalated cells of collecting duct, and on apical membranes in long thin limb of Henle loop.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|...
gi 258679518 23 KEKEMDPFHYDYQTLRIGGLVFAVVLFSVGILLILS-RRCKCS 64
Cdd:cd20323   1 DPKWDEPFTYDYETLRKAGLIIAAVLFITGILVLTCgKVCRLP 43

FXYD domain-containing ion transport regulator 12; The FXYD domain-containing ion transport regulator 12 (FXYD12) mRNA is mainly distributed in kidneys and intestines of fish. In co-immunoprecipitation experiments, FXYD12 was shown to associate with the Na(+)/(K+)-ATPase (NKA) alpha-subunit in the intestines of two closely related medakas, Oryzias dancena and O. latipes. These results suggests that FXYD12 may play a role in modulating NKA activity in the intestines following salinity changes in the maintenance of internal homeostasis.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 258679518 26 EMDP---FHYDYQTLRIGGLVFA--VVLFSVgILLI--LSRRCkcsFNQKPRAPGDE 75
Cdd:cd20330   1 DVDPdadFVYDYETLRIGGLIFAgvIVFLSV-LLLAgnKIRRC---GKPKPKPVEED 53