FXYD7, Mapping of Functional Sites Involved in Endoplasmic Reticulum Export, Association With and Regulation of Na,K-ATPase

Crambert, Gilles; Li, Ciming; Swee, Lee Kim; Geering, Käthi

doi:10.1074/jbc.m313494200

Cited by 42 publications

(51 citation statements)

References 35 publications

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“…In particular, Leu-964 and Phe-967 in TM9 contribute to the stable association, whereas Phe-956 and Glu-960 are involved in the transmission of the functional effect of FXYD proteins to Na,K-ATPase. Moreover, mutational analysis has revealed that the TM domain of FXYD7 plays a role in the structural and functional interaction of FXYD7 (6). Similar conclusions were drawn for FXYD2 and FXYD4 (7)(8)(9).…”

supporting

confidence: 65%

Role of the Transmembrane Domain of FXYD7 in Structural and Functional Interactions with Na,K-ATPase

Crambert

Thuillard

et al. 2005

Journal of Biological Chemistry

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Members of the FXYD family are tissue-specific regulators of the Na,K-ATPase. Here, we have investigated the contribution of amino acids in the transmembrane (TM) domain of FXYD7 to the interaction with Na,K-ATPase. Twenty amino acids of the TM domain were replaced individually by tryptophan, and combined mutations and alanine insertion mutants were constructed. Wild type and mutant FXYD7 were expressed in Xenopus oocytes with Na,KATPase. Mutational effects on the stable association with Na,KATPase and on the functional regulation of Na,K-ATPase were determined by co-immunoprecipitation and two-electrode voltage clamp techniques, respectively. Most residues important for the structural and functional interaction of FXYD7 are clustered in a face of the TM helix containing the two conserved glycine residues, but others are scattered over two-thirds of the FXYD TM helix. By using the free energy from the hydrolysis of one ATP molecule, Na,K-ATPase, a ubiquitous P-type ATPase, transports three Na ϩ out of the cell in exchange for two K ϩ into the cell. The minimal functional unit of Na,K-ATPase consists of a catalytic ␣ subunit and a regulatory ␤ subunit. Four ␣ and 3 ␤ isoforms exist and are expressed in a tissuespecific manner.The major physiological role of Na,K-ATPase is to create and maintain the Na ϩ /K ϩ gradient across the cell membrane, which is important for the maintenance of cell volume and membrane potential. Moreover, the Na ϩ gradient serves as an energy source for numerous secondary transport systems. Finally, Na,K-ATPase is essential for specialized functions of various tissues. In renal epithelial cells, Na,K-ATPase is exclusively expressed at the basolateral membrane and becomes the driving force for transepithelial Na ϩ reabsorption. In nervous tissue, Na,K-ATPase restores the Na ϩ and K ϩ gradients during action potentials and thus ensures neuronal excitability. In skeletal and heart muscle, the Na ϩ gradient coupled to Na ϩ /Ca 2ϩ exchanger activity controls the intracellular Ca 2ϩ concentration, which influences muscle contractility. The activity of Na,K-ATPase is subjected to short-and long-term regulation (1) mediated by the intracellular Na ϩ concentration, neurotransmitters, and hormones. Recently, members of the FXYD family (2) have been shown to be tissue-specific regulators of the Na,K-ATPase (3). FXYD proteins are small membrane proteins that are characterized by an N-terminal FXYD motif, two highly conserved glycine residues in the TM domain, and a serine residue at the cytoplasmic end of the TM domain. FXYD7, an O-glycosylated protein, is only expressed in brain, in both neurons and glial cells (4). FXYD7 associates with ␣␤1 isozymes, but not with ␣␤2 isozymes, when expressed in Xenopus oocytes. Stable association of FXYD7 with Na,K-ATPase modifies its apparent affinity for external K ϩ by increasing by ϳ2-fold the K1 ⁄ 2 value for K ϩ over a large range of membrane potentials in the presence and absence of external Na ϩ . In addition, FXYD7 modifies the apparent affinity for extrace...

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supporting

confidence: 65%

Role of the Transmembrane Domain of FXYD7 in Structural and Functional Interactions with Na,K-ATPase

Crambert

Thuillard

et al. 2005

Journal of Biological Chemistry

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“…The C-terminal valine is essential for ER export of HLA-F. Other immune system molecules such as CD8␣ (30), pro-TGF␣ (39,40), MTI-MPP (40), in addition to other proteins (31,41,42) also require a C-terminal valine to be captured into COPII vesicles for ER-to-Golgi transport. Because C-terminal valine residues are found in ϳ10% of human type I membrane proteins this feature may provide a general mechanism for ER export (33).…”

Section: Discussionmentioning

confidence: 99%

Selective Export of HLA-F by Its Cytoplasmic Tail

Boyle

Gillingham

Munro

et al. 2006

The Journal of Immunology

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MHC class I molecules exit the endoplasmic reticulum (ER) by an unknown mechanism. Although a selective export mechanism has been proposed for the anterograde transport of class I, a motif responsible for export has never been identified. Although classical class I molecules lacking their cytoplasmic tail are expressed on the cell surface, we found that HLA-F was entirely dependent on its cytoplasmic tail for export from the ER. Two known export motifs were recognizable in HLA-F. A C-terminal valine residue functioned in ER export and interacted with coat complex (COP)II, while an RxR motif also played an important role in anterograde transport and bound to 14-3-3 proteins. This divergent trafficking of HLA-F implicates an alternative function for HLA-F, independent of loading with peptides in the ER.

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“…Without knowing the functional activity of PLM, it is difficult to determine whether oligomerization is required for proper function. In addition to these signals, a carboxy-terminal valine residue appears to function as an ER export signal in several proteins, including FXYD7 (16,22,52). However, FXYD7 is the only FXYD family member with a carboxy-terminal valine, so this export signal does not play a role in trafficking of the other FXYD proteins.…”

Section: Subcellular Localization Of Plm Is Regulated By Phosphorylatmentioning

confidence: 99%

Cytoplasmic targeting signals mediate delivery of phospholemman to the plasma membrane

Lansbery

Burcea

Mendenhall³

et al. 2006

American Journal of Physiology-Cell Physiology

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FXYD7, Mapping of Functional Sites Involved in Endoplasmic Reticulum Export, Association With and Regulation of Na,K-ATPase

Cited by 42 publications

References 35 publications

Role of the Transmembrane Domain of FXYD7 in Structural and Functional Interactions with Na,K-ATPase

Role of the Transmembrane Domain of FXYD7 in Structural and Functional Interactions with Na,K-ATPase

Selective Export of HLA-F by Its Cytoplasmic Tail

Cytoplasmic targeting signals mediate delivery of phospholemman to the plasma membrane

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