TCDB is operated by the Saier Lab Bioinformatics Group
TCIDNameDomainKingdom/PhylumProtein(s)
1.A.27.1.1









Phospholemman (PLM; FXYD1) forms anion channels and regulates L-type Ca2+ channels as well as several other cation transport systems in cardiac myocytes (Zhang et al. 2015), most importantly the Na+,K+-ATPase (Pavlovic et al. 2013). Palmitoylation of the mammalian Na+ pump's accessory subunit PLM by the cell surface palmitoyl acyl transferase DHHC5 leads to pump inhibition, possibly by altering the relationship between the pump's catalytic α-subunit and specifically bound membrane lipids (Howie et al. 2018). PLM is also regulated by phosphorylation and glutathionylation (Pavlovic et al. 2013). and phosphorylation couteracts the inhibitory effect of palmitoylation (Cheung et al. 2013). The human ortholog has UniProt acc #O00168 and is 89% identical to the dog protein, with all of the difference occurring in the first 20 aas. Palmitoylation affects the regulation of cardiac electrophysiology, by modifying the sodium-calcium exchanger, phospholemman and the cardiac sodium pump, as well as the voltage-gated sodium channel (Essandoh et al. 2020). The conserved FXYD motif is found in this protein as residues 29-32.

Eukaryota
Metazoa
PLM of Canis familiaris
1.A.27.1.2









Cl- conductance inducer protein, Mat-8, of 88 aas and 1 TMS.

Eukaryota
Metazoa
Mat-8 of Mus musculus
1.A.27.1.3









FXYD6 regulator of Na,K-ATPase in the ear and taste buds, phosphohippolin, of 95 aas and 1 TMS (Delprat et al., 2007; Shindo et al., 2011).  It is expressed in the central nervous system (Kadowaki et al. 2004).

Eukaryota
Metazoa
FXYD6 of Homo sapiens (Q9H0Q3)
1.A.27.1.4









The sterol (dexamethasone, aldosterone) and low NaCl diet-inducible FXYD domain-containing ion transport regulator 4 precursor (Channel inducing factor, CHIF). It is an IsK-like MinK homologue (Attali et al., 1995). It regulates the Na+,K+-ATPase and the KCNQ1 channel protein as well as other ICNQ channels, opening them at all membrane potentials (Jespersen et al. 2006). CHIF as an indirect modulator of several different ion transport mechanisms, consistent with regulation of the Na+-K+-ATPase as the common denominator (Goldschmidt et al. 2004).

Eukaryota
Metazoa
CHIF of Rattus norvegicus
(Q63113)
1.A.27.1.5









FXYD3 (FXYD-3; Mat-8; PLML) with two splice variants, one of 87 aas with 2 TMSs (an N-terminal leader sequence and a central very hydrophobic TMS) and the other of 116 aas and 2 TMSs (Bibert et al. 2006).  Both FXYD3 variants co-immunoprecipitate with the Na,K-ATPase. They both associate stably with Na,K-ATPase isozymes but not with the H,K-ATPase or Ca-ATPase. The short human FXYD3 has 72% sequence identity with mouse FXYD3, whereas long human FXYD3 is identical to the short human FXYD3 but has a 26-amino acid insertion after the transmembrane domain. Short and long human FXYD3 RNAs and proteins are differentially expressed during differentiation with long FXYD3 being mainly expressed in nondifferentiated cells while short FXYD3 is expressed in differentiated cells (Bibert et al. 2006). Overexpression of FXYD3, as it occurs in pancreatic cancer, may contribute to the proliferative activity of this malignancy (Kayed et al. 2006).

Eukaryota
Metazoa
FXYD3 of Homo sapiens
1.A.27.1.6









FXYD4 of 89 aas and 1 TMS.

Eukaryota
Metazoa
FXYD4 of Homo sapiens
1.A.27.1.7









FXYD7 of 80 aas and 1 TMS. The TMS mediates the complex interactions with the Na,K-ATPase (Li et al. 2005). The brain-specific FXYD7 is a member of the FXYD family that associates with the alpha1-beta1 Na,K-ATPase isozyme and induces a 2-fold decrease in its apparent K+ affinity. In contrast to FXYD2 and FXYD4, the conserved FXYD motif in the extracytoplasmic domain is not involved in the association of FXYD7 with the Na,K-ATPase. The conserved Gly40 and Gly29, located on the same face of the TMS, were implicated in the association with and the regulation of Na,K-ATPase (Crambert et al. 2004). The C-terminal valine residue is involved in  ER export of FXYD7. FXYDs are a vertebrate innovation and an important site of hormonal action (Pirkmajer and Chibalin 2019).

Eukaryota
Metazoa
FXYD7 of Homo sapiens
1.A.27.1.8









Phospholemman, FXYD1 or PLM of 92 aas and 1 TMS.  See 1.A.27.1.1 for details for the dog ortholog. Palmitoylation affects the regulation of cardiac electrophysiology, by modifying the sodium-calcium exchanger, phospholemman and the cardiac sodium pump, as well as the voltage-gated sodium channel (Essandoh et al. 2020). Palmitoylation of PLM inhibits the Na+ K+-ATPase while phosphorylation reverses this inhibition. The conserved FXYD motif is found in this protein at residues 29-32 (Cheung et al. 2013).

Eukaryota
Metazoa
PLM of Homo sapiens
1.A.27.2.1









γ-subunit (proteolipid) of Na+,K+-ATPase, FXYD2.   Also functions as a cation-selective channel (Sha et al. 2008).

Eukaryota
Metazoa
FXYD2 channel and γ-subunit of the Na+,K+-ATPase of Homo sapiens
1.A.27.2.2









Sodium/potassium-transporting ATPase subunit gamma isoform X1of 82 aas and 1 TMS.

Eukaryota
Metazoa
γ-subunit of Pseudopodoces humilis
1.A.27.2.3









Sodium/potassium-transporting ATPase subunit gamma of 61 aas and 1 TMS.

Eukaryota
Metazoa
γ-subunit of Xenopus tropicalis (tropical clawed frog)
1.A.27.2.4









Sodium/potassium-transporting ATPase subunit gamma isoform X1

Eukaryota
Metazoa
Na+, K+-ATPase regulator of Mus pahari (shrew mouse)
1.A.27.2.5









Sodium/potassium-transporting ATPase subunit gamma isoform X1of 65 aas and 1 TMS.  The 3-d structure of a 31 aa peptide including the single TMS is available (PDB# 2N23).

Eukaryota
Metazoa
γ-subunit of Sus scrofa (pig)
1.A.27.3.1









FXYD5 regulator of Na,K+-ATPase and ion channel activities of 178 aas and 1 C-terminal TMS.  FXYD5 interacts directly with the Na+,K+-ATPase via their TMSs to affect the Vmax of the latter, and residues involved have been identified (Lubarski et al. 2007).

Eukaryota
Metazoa
FXYD5 of Homo sapiens (178 aas; Q96DB9)
1.A.27.3.2









FXYD domain-containing ion transport regulator 5-like isoform X2 of 89 aas and 2 TMSs.

Eukaryota
Metazoa
FXYD regulator of Ornithorhynchus anatinus (platypus)
1.A.27.3.3









FXYD domain-containing ion transport regulator 5-like isoform X1 of 101 aas and 2 TMSs, N- and C-terminal.  TC Blast with this protein retrieves 1.G.12.2.3 with about 90 residues aligning with 29% identity and 45% similarity.  These two families may be related.

Eukaryota
Metazoa
FXYD domain protein of Carassius auratus (goldfish)
1.A.27.3.4









FXYD domain-containing ion transport regulator 5-like isoform X2 of 174 aas and 2 TMSs, N- and C-terminal.

Eukaryota
Metazoa
FXYD domain protein of Denticeps clupeoides (denticle herring)
1.A.27.3.5









FXYD domain-containing ion transport regulator 5-like isoform X2 of 170aas and 2 TMSs.

Eukaryota
Metazoa
FXYD domain protein of Rhinatrema bivittatum (two-lined caecilian)