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        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1814654166 122 PQEPDPFYYDYDTVQTVGMTLATILFLLGILFIVSKKMKCRKADSRSESPT 172
Cdd:cd20325     1 FEDQSPFEYDYETLRTTGVILAVVMFVLGILIALSKKFKCKKSDSSKSLLR 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        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1814654166 122 PQEPDPFYYDYDTVQTVGMTLATILFLLGILFIVSKKMKCRKADSRSESPT 172
Cdd:cd20325     1 FEDQSPFEYDYETLRTTGVILAVVMFVLGILIALSKKFKCKKSDSSKSLLR 51

ATP1G1/PLM/MAT8 family;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1814654166  25 EHDPFTYDYQSLRIGGLIIAGILFILGILIILSRRCRCKFNQQQRT 70
Cdd:pfam02038   2 EDDPFYYDYETLRIGGLIFAGLLFIVGILIILSKKCKCKFNQKPRS 47

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        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1814654166 122 PQEPDPFYYDYDTVQTVGMTLATILFLLGILFIVSKKMKCRKADSRSESPT 172
Cdd:cd20325     1 FEDQSPFEYDYETLRTTGVILAVVMFVLGILIALSKKFKCKKSDSSKSLLR 51

FXYD domain-containing ion transport regulator 6; FXYD domain-containing ion transport regulator 6 (FXYD6 encodes the protein phosphohippolin and is located at the 11q23.3. It can be found in all human tissues except blood. FXYD6 in humans is primarily in the brain, with highest levels of expression found in the prefrontal cortex, amygdala, hypothalamus, and occipital lobe. FXYD6 is up-regulated in hepatocellular carcinoma (HCC) and it enhances the migration and proliferation of HCC cells. Therapy targeting FXYD6 could potentially benefit the clinical treatment toward HCC patients. FXYD6 is also associated with mental diseases. Mutations in the FXYD6 gene, or in sequences close to this gene, can predispose to schizophrenia which is known to be strongly heritable. FXYD6 was also found to be significantly downregulated in a Tg2576 mouse model of Alzheimer's disease (AD) brain and hippocampus. FXYD6 is a novel regulator of Na,K-ATPase expressed in the inner ear.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1814654166   4 LSHILVLC---VGLLAMVNAEAPQEHDPFTYDYQSLRIGGLIIAGILFILGILIILSRRCRCKFNQ 66
Cdd:cd20324     1 LTVLVALCswlVPALASAADEKKDEDSPFHYDYESLRIGGLVFAVVLFLLGILLILSRKCRCSFNQ 66

FXYD domain-containing ion transport regulator 1; FXYD domain-containing ion transport regulator 1 (FXYD1), also known as phospholemman (PLM), or sodium/potassium-transporting ATPase subunit FXYD1, 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. It is a plasma membrane substrate for several kinases, including protein kinase A, protein kinase C, NIMA kinase, and myotonic dystrophy kinase. It is thought to form an ion channel or regulate ion channel activity. Transcript variants with different 5' UTR sequences have been described in the literature.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|.
gi 1814654166 122 PQEPDPFYYDYDTVQTVGMTLATILFLLGILFIVSKKMKCR 162
Cdd:cd20317     1 PQEHDPFTYDYQSLRIGGLIIAGILFILGILIILSRRCRCK 41

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 1814654166   7 ILVLCVGLLAMVNAEAPQ---EHDPFTYDYQSLRIGGLIIAGILFILGILIILSRRCRCKFNQQQRtgEPDEEEGTFRSS 83
Cdd:cd20327     4 LIFVCSLLIPVVLASAAKkekEIDPFHYNYQTLRIGGLVFDMVLFLVLSLHLLSHRCKCSFNQKPQ--DPGDEEAQVENF 81

                  .
gi 1814654166  84 I 84
Cdd:cd20327    82 I 82

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
                  ....*....|....*....|....*....|....*....|....*..
gi 1814654166  23 PQEHDPFTYDYQSLRIGGLIIAGILFILGILIILSRRCRCKFNQQQR 69
Cdd:cd20328     5 EDKDSPFYYDWHRLRVGGLICAAVLCAIGIIVLLSGKCKCKFNQKKR 51

FXYD domain-containing ion transport regulator 2; FXYD domain-containing ion transport regulator 2 (FXYD2), also known as sodium/potassium-transporting ATPase subunit gamma, or Na(+)/K(+) ATPase subunit gamma, or sodium pump gamma chain, is the regulatory subunit of the sodium/potassium-transporting ATPase (Na,K-ATPase). Na+,K+-ATPase is a heteromeric complex consisting of a large alpha-subunit, which is responsible for ATP hydrolysis, ion transport, and CTS binding, and a beta-subunit, acting as a chaperone. Although the Na,K-ATPase does not depend on the gamma subunit to be functional, it is thought that the gamma subunit modulates the enzyme's activity by inducing ion channel activity. Mutations in this gene have been associated with renal hypomagnesaemia.

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 1814654166 123 QEPDPFYYDYDTVQTVGMTLATILFLLGILFIVSKKMKC 161
Cdd:cd20318     5 GSEDPFTYDYETVRNGGLIFAAVAFVVGLLIILSKRFRC 43

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
                  ....*....|....*....|....*....|....*....|....*..
gi 1814654166 122 PQEPDPFYYDYDTVQTVGMTLATILFLLGILFIVSKKMKCRKADSRS 168
Cdd:cd20328     5 EDKDSPFYYDWHRLRVGGLICAAVLCAIGIIVLLSGKCKCKFNQKKR 51

FXYD domain-containing ion transport regulator 11; FXYD domain-containing ion transport regulator 11 (FXYD11) is a putative regulatory subunit of the Na(+)/K(+)-ATPase (NKA) pump. FXYD11 is expressed predominantly in the gills of euryhaline teleosts, such as the spotted scat, Scatophagus argus. It regulates NKA activity through protein-protein interactions. The regulation of NKA and FXYD11 is of critical importance for osmotic homeostasis. The expression and activity of NKA, as well as FXYD11 mRNA expression in gills have been shown to respond to different environmental salinity by dual-labeling immunohistochemistry and quantitative PCR (RT-qPCR) methods, indicating that there is an interaction between NKA and FXYD.

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                  ....*....|....*....|....*....|....*....|....
gi 1814654166   1 MASLSHILVLCVGLLAMVNAEApqehDPFTYDYQSLRIGGLIIA 44
Cdd:cd20329     1 MGHLTLVAVLAVLFSLFMETEA----NPFVYNYERLRIGGLVFA 40

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
                  ....*....|....*.
gi 1814654166  29 FTYDYQSLRIGGLIIA 44
Cdd:cd20277     1 FYYDYETLRIGGLVFA 16

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.

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                  ....*....|....*....|...
gi 1814654166  25 EHDP---FTYDYQSLRIGGLIIA 44
Cdd:cd20330     1 DVDPdadFVYDYETLRIGGLIFA 23