A functional interaction between CHIF and Na-K-ATPase: implication for regulation by FXYD proteins

Garty, Haim; Lindzen, Moshit; Scanzano, Rosemarie; Айзман, Р. И.; Füzesi, Maria; Goldshleger, Rivka; Farman, Nicolette; Blostein, Rhoda; Karlish, Steven J. D.

doi:10.1152/ajprenal.00112.2002

Cited by 80 publications

(119 citation statements)

References 29 publications

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“…Effects on the extracellular K ϩ affinity of both splice variants of ␥ have also been reported (11,59). Co-expression of the FXYD4 protein CHIF with rat ␣1 increased the apparent affinity for cytoplasmic Na ϩ , without affecting the K ϩ affinity or V max (23,66). It should be noted, however, that assignment of changes in apparent ion affinities from steady-state measurements to specific steps in the reaction mechanism might be difficult.…”

Section: Discussionmentioning

confidence: 95%

Regulation of Na,K-ATPase by PLMS, the Phospholemman-like Protein from Shark

Mahmmoud

Cramb

Maunsbach

et al. 2003

Journal of Biological Chemistry

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In Na,K-ATPase membrane preparations from shark rectal glands, we have previously identified an FXYD domain-containing protein, phospholemman-like protein from shark, PLMS. This protein was shown to associate and modulate shark Na,K-ATPase activity in vitro. Here we describe the complete coding sequence, expression, and cellular localization of PLMS in the rectal gland of the shark Squalus acanthias. The mature protein contained 74 amino acids, including the N-terminal FXYD motif and a C-terminal protein kinase multisite phosphorylation motif. The sequence is preceded by a 20 amino acid candidate cleavable signal sequence. Immunogold labeling of the Na,K-ATPase ␣-subunit and PLMS showed the presence of ␣ and PLMS in the basolateral membranes of the rectal gland cells and suggested their partial colocalization. Furthermore, through controlled proteolysis, the C terminus of PLMS containing the protein kinase phosphorylation domain can be specifically cleaved. Removal of this domain resulted in stimulation of maximal Na,K-ATPase activity, as well as several partial reactions. Both the E 1 ϳP 3 E 2 -P reaction, which is partially rate-limiting in shark, and the K ؉ deocclusion reaction, E 2 (K) 3 E 1 , are accelerated. The latter may explain the finding that the apparent Na ؉ affinity was increased by the specific C-terminal PLMS truncation. Thus, these data are consistent with a model where interaction of the phosphorylation domain of PLMS with the Na,K-ATPase ␣-subunit is important for the modulation of shark Na,K-ATPase activity.

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Section: Discussionmentioning

confidence: 95%

Regulation of Na,K-ATPase by PLMS, the Phospholemman-like Protein from Shark

Mahmmoud

Cramb

Maunsbach

et al. 2003

Journal of Biological Chemistry

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“…Transport assays were carried out on cells grown in 24-well plates as described in ref. 18. Kinetic constants were determined by fitting the data to either a simple one-site Michaelis-Menten model (KЈ ATP ), or a two-site (K 0.…”

Section: Methodsmentioning

confidence: 99%

Alterations in the α2 isoform of Na,K-ATPase associated with familial hemiplegic migraine type 2

Segall

Mezzetti

Scanzano

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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A number of missense mutations in the Na,K-ATPase ␣2 catalytic subunit have been identified in familial hemiplegic migraine with aura. Two alleles (L764P and W887R) showed loss-of-function, whereas a third (T345A) is fully functional but with altered Na,KATPase kinetics. This study describes two additional mutants, R689Q and M731T, originally identified by Vanmolkot et al. , which we show here to also be functional and kinetically altered. Both mutants have reduced catalytic turnover and increased apparent affinity for extracellular K ؉ . For both R689Q and M731T, sensitivity to vanadate inhibition is decreased, suggesting that the steadystate E 1 7 E2 poise of the enzyme is shifted toward E1. Whereas the K ATP is not affected by the R689Q replacement, the M731T mutant has an increase in apparent affinity for ATP. Analysis of the structural changes effected by T345A, R689Q, and M731T mutations, based on homologous replacements in the known crystal structure of the sarcoplasmic reticulum Ca-ATPase, provides insights into the molecular bases for the kinetic alterations. It is suggested that the disease phenotype is the consequence of lowered molecular activity of the ␣2 pump isoform due to either decreased K ؉ affinity (T345A) or catalytic turnover (R689Q and M731T), thus causing a delay in extracellular K ؉ clearance and͞or altered localized Ca 2؉ handling͞signaling secondary to reduced activity in colocalized Na ؉ ͞Ca 2؉ exchange.sodium pump kinetics ͉ missense mutations ͉ ATP1A2 gene T he Na,K-ATPase catalyzes the ATP-driven exchange of three intracellular Na ϩ ions for two extracellular K ϩ ions across the plasma membrane of virtually all animal cells and is essential to the maintenance of the electrochemical alkali cation gradients that are dissipated by ion channels in the propagation of action potentials (for recent reviews, see refs. 1 and 2). The catalytic cycle of this P type ion pump involves phosphorylation and dephosphorylation of a conserved aspartate residue in its catalytic ␣ subunit and conformational transitions of phosphoand dephosphoenzyme, commonly referred to as E 1 P 7 E 2 P and E 1 7 E 2 conformational transitions, respectively (see Scheme 1). Four isoforms of ␣ and three isoforms of ␤ have been described thus far. All are distributed in a tissue-and developmentally dependent manner. In adult mammals, ␣2 is located principally in skeletal muscle and brain, in particular in glial cells, and, to a lesser extent, in heart, adipocytes, and the eye (see refs. 3-6).The discovery of the association of missense mutations in the ATP1A2 gene on chromosome 1q23 that encodes the Na,KATPase ␣2 isoform with familial hemiplegic migraine (FHM) has been an important breakthrough in that it reflects a disease caused by a kinetically altered sodium pump and is therefore an important lead in migraine pathophysiology. Although a migraine is a common polygenic disorder, FHM is a rare autosomal dominant form of migraine with aura and is usually additionally associated with hemiparesis and other clinical features ...

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“…FXYD2 or the ␥ subunit of Na,K-ATPase (8) was the first FXYD protein that was identified as a specific modulator of renal Na,K-ATPase (9 -13). It is now well established that also FXYD1 (phospholemman) (14), a phospholemman-like protein from shark (15), FXYD4 (corticosteroid hormone-induced factor) (11,16), and FXYD7 (17) also play a tissue-specific role in Na,K-ATPase regulation. Significantly, each of these auxiliary subunits produce a distinct functional effect on Na,K-ATPase that is adapted to the physiological needs of the tissues in which they are expressed.…”

mentioning

confidence: 99%

Structural and Functional Interaction Sites between Na,K-ATPase and FXYD Proteins

Grosdidier

Crambert

et al. 2004

Journal of Biological Chemistry

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Several members of the FXYD protein family are tissue-specific regulators of Na,K-ATPase that produce distinct effects on its apparent K ؉ and Na ؉ affinity. Little is known about the interaction sites between the Na,KATPase ␣ subunit and FXYD proteins that mediate the efficient association and/or the functional effects of FXYD proteins. In this study, we have analyzed the role of the transmembrane segment TM9 of the Na,K-ATPase ␣ subunit in the structural and functional interaction with FXYD2, FXYD4, and FXYD7. Mutational analysis combined with expression in Xenopus oocytes reveals that Phe 956 , Glu 960 , Leu 964 , and Phe 967 in TM9 of the Na,K-ATPase ␣ subunit represent one face interacting with the three FXYD proteins. Leu 964 and Phe 967 contribute to the efficient association of FXYD proteins with the Na,K-ATPase ␣ subunit, whereas Phe 956 and Glu 960 are essential for the transmission of the functional effect of FXYD proteins on the apparent K ؉ affinity of Na,K-ATPase. The relative contribution of Phe 956 and Glu 960 to the K ؉ effect differs for different FXYD proteins, probably reflecting the intrinsic differences of FXYD proteins on the apparent K ؉ affinity of Na,K-ATPase. In contrast to the effect on the apparent K ؉ affinity, Phe 956 and Glu 960 are not involved in the effect of FXYD2 and FXYD4 on the apparent Na ؉ affinity of Na,K-ATPase. The mutational analysis is in good agreement with a docking model of the Na,K-ATPase/ FXYD7 complex, which also predicts the importance of Phe 956 , Glu 960 , Leu 964 , and Phe 967 in subunit interaction. In conclusion, by using mutational analysis and modeling, we show that TM9 of the Na,K-ATPase ␣ subunit exposes one face of the helix that interacts with FXYD proteins and contributes to the stable interaction with FXYD proteins, as well as mediating the effect of FXYD proteins on the apparent K ؉ affinity of Na,K-ATPase.

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A functional interaction between CHIF and Na-K-ATPase: implication for regulation by FXYD proteins

Cited by 80 publications

References 29 publications

Regulation of Na,K-ATPase by PLMS, the Phospholemman-like Protein from Shark

Regulation of Na,K-ATPase by PLMS, the Phospholemman-like Protein from Shark

Alterations in the α2 isoform of Na,K-ATPase associated with familial hemiplegic migraine type 2

Structural and Functional Interaction Sites between Na,K-ATPase and FXYD Proteins

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