FXYD Protein Family Research Articles

FXYD7, the first brain- and isoform-specific regulator of Na,K-ATPase: biosynthesis and function of its posttranslational modifications.

The FXYD protein family has recently been defined as a result of the search for homologues of the Na,K-ATPase gamma subunit, CHIF, and phospholemman in EST and gene data banks. FXYD7 has been seen to have a role as a brain- and isozyme-specific regulator of Na/K-ATPase. In this study, the biosynthesis, membrane topology, nature, and role of the processing of FXYD7 are investigated.

FXYD proteins: new tissue- and isoform-specific regulators of Na,K-ATPase.

The recently defined FXYD protein family contains seven members that are small, single-span membrane proteins characterized by a signature sequence containing an FXYD motif and three other conserved amino acid residues. Until recently, the functional role of FXYD proteins was largely unknown, with the exception of the gamma subunit of Na,K-ATPase, which was shown to be a specific regulator of renal alpha1-beta1 isozymes. We have investigated whether other members of the FXYD family may have a similar role as the gamma subunit and have found that CHIF (corticosteroid hormone-induced factor, FXYD4), FXYD7, as well as phospholemman (FXYD1) specifically associate with Na,K-ATPase and preferentially with alpha1-beta isozymes in native tissues, and produce distinct effects on the transport properties of Na,K-ATPase that are adapted to the physiological demands of the tissues in which they are expressed. These results provide evidence for a unique and novel mode of regulation of Na,K-ATPase by FXYD proteins that involves a tissue-specific expression of an auxiliary subunit of distinct Na,K-ATPase isozymes.

Themes in ion pump regulation.

The Na,K-ATPase is an ion pump present in the plasma membrane. It is of vital importance for cell and body homeostasis and as such is under strict hormonal control. The molecular basis for the acute regulation of Na,K-ATPase is multisite phosphorylation by protein kinases that can alter its behavior. This includes direct effects on the Na,K-ATPase activity, regulation by membrane trafficking, and even dynamic regulation of interaction with regulatory proteins. In shark Na,K-ATPase, the latter includes functional interaction with a small hydrophobic protein of the FXYD protein family, phospholemman-like protein from shark, PLMS. This article summarizes our recent work on the mechanisms involved in the acute regulation of the Na,K-ATPase studied using a plasma membrane preparation from shark salt glands as an epithelial transport model.

CHIF, a member of the FXYD protein family, is a regulator of Na,K-ATPase distinct from the gamma-subunit.

The biological role of small membrane proteins of the new FXYD family is largely unknown. The best characterized FXYD protein is the gamma-subunit of the Na,K-ATPase (NKA) that modulates the Na,K-pump function in the kidney. Here, we report that, similarly to gamma(a) and gamma(b) splice variants, the FXYD protein CHIF (corticosteroid-induced factor) is a type I membrane protein which is associated with NKA in renal tissue, and modulates the Na,K-pump transport when expressed in Xenopus oocytes. In contrast to gamma(a) and gamma(b), which both decrease the apparent Na+ affinity of the Na,K-pump, CHIF significantly increases the Na+ affinity and decreases the apparent K+ affinity due to an increased Na+ competition at external binding sites. The extracytoplasmic FXYD motif is required for stable gamma-subunit and CHIF interaction with NKA, while cytoplasmic, positively charged residues are necessary for the gamma-subunit's association efficiency and for CHIF's functional effects. These data document that CHIF is a new tissue-specific regulator of NKA which probably plays a crucial role in aldosterone-responsive tissues responsible for the maintenance of body Na+ and K+ homeostasis.