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• W1987482305 abstract "Membrane pyrophosphatases (PPases), divided into K+-dependent and K+-independent subfamilies, were believed to pump H+ across cell membranes until a recent demonstration that some K+-dependent PPases function as Na+ pumps. Here, we have expressed seven evolutionarily important putative PPases in Escherichia coli and estimated their hydrolytic, Na+ transport, and H+ transport activities as well as their K+ and Na+ requirements in inner membrane vesicles. Four of these enzymes (from Anaerostipes caccae, Chlorobium limicola, Clostridium tetani, and Desulfuromonas acetoxidans) were identified as K+-dependent Na+ transporters. Phylogenetic analysis led to the identification of a monophyletic clade comprising characterized and predicted Na+-transporting PPases (Na+-PPases) within the K+-dependent subfamily. H+-transporting PPases (H+-PPases) are more heterogeneous and form at least three independent clades in both subfamilies. These results suggest that rather than being a curious rarity, Na+-PPases predominantly constitute the K+-dependent subfamily. Furthermore, Na+-PPases possibly preceded H+-PPases in evolution, and transition from Na+ to H+ transport may have occurred in several independent enzyme lineages. Site-directed mutagenesis studies facilitated the identification of a specific Glu residue that appears to be central in the transport mechanism. This residue is located in the cytoplasm-membrane interface of transmembrane helix 6 in Na+-PPases but shifted to within the membrane or helix 5 in H+-PPases. These results contribute to the prediction of the transport specificity and K+ dependence for a particular membrane PPase sequence based on its position in the phylogenetic tree, identity of residues in the K+ dependence signature, and position of the membrane-located Glu residue. Membrane pyrophosphatases (PPases), divided into K+-dependent and K+-independent subfamilies, were believed to pump H+ across cell membranes until a recent demonstration that some K+-dependent PPases function as Na+ pumps. Here, we have expressed seven evolutionarily important putative PPases in Escherichia coli and estimated their hydrolytic, Na+ transport, and H+ transport activities as well as their K+ and Na+ requirements in inner membrane vesicles. Four of these enzymes (from Anaerostipes caccae, Chlorobium limicola, Clostridium tetani, and Desulfuromonas acetoxidans) were identified as K+-dependent Na+ transporters. Phylogenetic analysis led to the identification of a monophyletic clade comprising characterized and predicted Na+-transporting PPases (Na+-PPases) within the K+-dependent subfamily. H+-transporting PPases (H+-PPases) are more heterogeneous and form at least three independent clades in both subfamilies. These results suggest that rather than being a curious rarity, Na+-PPases predominantly constitute the K+-dependent subfamily. Furthermore, Na+-PPases possibly preceded H+-PPases in evolution, and transition from Na+ to H+ transport may have occurred in several independent enzyme lineages. Site-directed mutagenesis studies facilitated the identification of a specific Glu residue that appears to be central in the transport mechanism. This residue is located in the cytoplasm-membrane interface of transmembrane helix 6 in Na+-PPases but shifted to within the membrane or helix 5 in H+-PPases. These results contribute to the prediction of the transport specificity and K+ dependence for a particular membrane PPase sequence based on its position in the phylogenetic tree, identity of residues in the K+ dependence signature, and position of the membrane-located Glu residue. IntroductionMembrane pyrophosphatases (PPases 2The abbreviations used are: PPasepyrophosphataseCh-PPaseC. hydrogenoformans PPaseAc-PPaseA. caccae PPaseCl-PPaseC. limicola PPaseCt-PPaseC. thermocellum PPaseDa-PPaseD. acetoxidans PPaseFj-PPaseF. johnsoniae PPaseLb-PPaseL. biflexa PPasePa-PPaseP. aerophilum PPaseCtet-PPaseC. tetani PPaseTm-PPaseT. maritima PPaseIMVinner membrane vesicle(s)TMAtetramethylammoniumTMHtransmembrane helix.; EC 3.6.1.1; Transporter Classification Database number 3.A.10) couple the hydrolysis of PPi to the active transport of cations across membranes and display no sequence homology to any known protein family. Membrane PPases consist of 70–81-kDa subunits that apparently form a homodimer (1Maeshima M. Biochim. Biophys. Acta. 2000; 1465: 37-51Crossref PubMed Scopus (370) Google Scholar) and are divided into K+-dependent and K+-independent subfamilies. The key determinant of K+ dependence is a single amino acid position located near the cytoplasm-membrane interface, which is occupied by Ala in the K+-dependent and Lys in the K+-independent enzymes (2Belogurov G.A. Lahti R. J. Biol. Chem. 2002; 277: 49651-49654Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). All PPases additionally require Mg2+ for function (3Baykov A.A. Bakuleva N.P. Rea P.A. Eur. J. Biochem. 1993; 217: 755-762Crossref PubMed Scopus (65) Google Scholar).H+-transporting PPases (H+-PPases), discovered >40 years ago, are widespread among organisms in all three domains of life (4Baltscheffsky M. Nature. 1967; 216: 241-243Crossref PubMed Scopus (78) Google Scholar, 5Baltscheffsky H. Von Stedingk L.V. Heldt H.W. Klingenberg M. Science. 1966; 153: 1120-1122Crossref PubMed Scopus (141) Google Scholar, 6Serrano A. Pérez-Castiñeira J.R. Baltscheffsky M. Baltscheffsky H. IUBMB Life. 2007; 59: 76-83Crossref PubMed Scopus (81) Google Scholar). Both K+-dependent and K+-independent H+-PPases have been characterized. In bacteria and archaea, these enzymes generate an ion-motive force for ATP synthesis and transport processes, particularly during stress and low energy conditions (7Baltscheffsky M. Schultz A. Baltscheffsky H. FEBS Lett. 1999; 457: 527-533Crossref PubMed Scopus (108) Google Scholar, 8López-Marqués R.L. Pérez-Castiñeira J.R. Losada M. Serrano A. J. Bacteriol. 2004; 186: 5418-5426Crossref PubMed Scopus (40) Google Scholar, 9García-Contreras R. Celis H. Romero I. J. Bacteriol. 2004; 186: 6651-6655Crossref PubMed Scopus (25) Google Scholar). In eukaryotes, H+-PPase acts in parallel with H+-ATPase and plays important roles in securing acidity and thus the functionality of cellular organelles, such as vacuoles in plants (1Maeshima M. Biochim. Biophys. Acta. 2000; 1465: 37-51Crossref PubMed Scopus (370) Google Scholar, 6Serrano A. Pérez-Castiñeira J.R. Baltscheffsky M. Baltscheffsky H. IUBMB Life. 2007; 59: 76-83Crossref PubMed Scopus (81) Google Scholar, 10Drozdowicz Y.M. Rea P.A. Trends Plant Sci. 2001; 6: 206-211Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar) and acidocalcisomes in protozoa (11Docampo R. de Souza W. Miranda K. Rohloff P. Moreno S.N. Nat. Rev. Microbiol. 2005; 3: 251-261Crossref PubMed Scopus (344) Google Scholar). In plants, H+-PPase appears to be involved in auxin-dependent organ development (12Fukuda A. Tanaka Y. Plant Physiol. Biochem. 2006; 44: 351-358Crossref PubMed Scopus (61) Google Scholar, 13Li J. Yang H. Peer W.A. Richter G. Blakeslee J. Bandyopadhyay A. Titapiwantakun B. Undurraga S. Khodakovskaya M. Richards E.L. Krizek B. Murphy A.S. Gilroy S. Gaxiola R. Science. 2005; 310: 121-125Crossref PubMed Scopus (339) Google Scholar), and overexpression of the pump in agricultural plants confers resistance against water/nutrient deprivation, cold, and salinity (14Zhang J. Li J. Wang X. Chen J. Plant Physiol. Biochem. 2011; 49: 33-38Crossref PubMed Scopus (51) Google Scholar, 15Lv S. Zhang K. Gao Q. Lian L. Song Y. Zhang J. Plant Cell Physiol. 2008; 49: 1150-1164Crossref PubMed Scopus (139) Google Scholar, 16Li B. Wei A. Song C. Li N. Zhang J. Plant Biotechnol. J. 2008; 6: 146-159Crossref PubMed Scopus (100) Google Scholar, 17Park S. Li J. Pittman J.K. Berkowitz G.A. Yang H. Undurraga S. Morris J. Hirschi K.D. Gaxiola R.A. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 18830-18835Crossref PubMed Scopus (222) Google Scholar). Furthermore, H+-PPase is a promising drug target in protozoan parasites (18Docampo R. Moreno S.N. Curr. Pharm. Des. 2008; 14: 882-888Crossref PubMed Scopus (58) Google Scholar).In contrast, Na+-transporting PPases (Na+-PPases) were only recently identified in the mesophilic archaeon Methanosarcina mazei, the moderately thermophilic acetogenic bacterium Moorella thermoacetica, and the marine hyperthermophilic bacterium Thermotoga maritima (19Malinen A.M. Belogurov G.A. Baykov A.A. Lahti R. Biochemistry. 2007; 46: 8872-8878Crossref PubMed Scopus (47) Google Scholar). These enzymes are similar to the H+-PPases in many aspects but require both K+ and Na+ for activity (20Belogurov G.A. Malinen A.M. Turkina M.V. Jalonen U. Rytkönen K. Baykov A.A. Lahti R. Biochemistry. 2005; 44: 2088-2096Crossref PubMed Scopus (26) Google Scholar).The initial discovery of Na+-PPases in the contrasting ecological and evolutionary niches suggests that PPi-energized Na+ transport is a ubiquitous process. However, verification of this hypothesis has been severely hampered by our inability to predict transport specificity directly from protein sequence information. In this study, we overcame this limitation by experimentally screening transport specificity across different types of membrane PPases. These data, in conjugation with phylogenetic analysis, indicate that Na+ transport specificity is indeed a very common property and preceded H+ transport specificity in the evolutionary history of the protein family. We additionally employed site-directed mutagenesis to identify the structural elements defining membrane PPase transport specificity.DISCUSSIONThe membrane PPase family consists of two independently evolving subfamilies, one (K+-dependent) requiring millimolar concentrations of K+ to attain catalytic activity and the other being K+-independent (2Belogurov G.A. Lahti R. J. Biol. Chem. 2002; 277: 49651-49654Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). Both subfamilies were originally believed to operate as H+ pumps until the recent discovery of Na+-PPases within the K+-dependent subfamily (19Malinen A.M. Belogurov G.A. Baykov A.A. Lahti R. Biochemistry. 2007; 46: 8872-8878Crossref PubMed Scopus (47) Google Scholar). The four novel Na+-PPases uncovered in this study have further increased the total number of identified Na+-PPases to seven. Moreover, Biegel and Müller (37Biegel E. Müller V. J. Biol. Chem. 2011; 286: 6080-6084Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar) recently reported PPi-dependent Na+ accumulation in IMV prepared from Acetobacterium woodii, suggesting that this bacterium also contains a Na+-PPase. Notably, Ctet-PPase was previously reported to operate as a H+ pump (38Huang Y.T. Liu T.H. Chen Y.W. Lee C.H. Chen H.H. Huang T.W. Hsu S.H. Lin S.M. Pan Y.J. Lee C.H. Hsu I.C. Tseng F.G. Fu C.C. Pan R.L. J. Biol. Chem. 2010; 285: 23655-23664Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar). We did not observe a PPi-induced H+ transport signal with Ctet-PPase IMV but detected a strong Na+ transport signal. Ctet-PPase has thus been classified as a Na+ pump, consistent with the findings that C. tetani employs Na+ as the major coupling ion for membrane transport processes, lacks primary H+ pumps, and has a V-type Na+-coupled ATPase instead of H+-ATPase (39Bruggemann H. Baumer S. Fricke W.F. Wiezer A. Liesegang H. Decker I. Herzberg C. Martinez-Arias R. Merkl R. Henne A. Gottschalk G. Proc. Natl. Acad. Sci. U.S.A. 2003; 100: 1316-1321Crossref PubMed Scopus (286) Google Scholar).K+-dependent PPases can be phylogenetically classified into four major clades rooting at nodes A, B, C, and D (Fig. 1). Clade A branches at the interface of K+-dependent and K+-independent subfamilies, whereas clades B, C, and D group monophyletically at node N further within the K+-dependent subfamily. Clade A contains H+-PPases, clades B and C are populated by Na+-PPases, and clade D possesses both H+- and Na+-PPases. Na+-PPases thus dominate the K+-dependent subfamily, whereas Na+ pumping and dependence are traced to node N and thus are considered as an ancestor of the N cluster (groups of clades B, C, and D). At the functional level, the monophyletic origin of all existing Na+-PPases is supported by the finding that the activities of the enzymes characterized are regulated similarly by a complex Na+- and K+-dependent mechanism affecting both maximal enzymatic activity and ligand binding affinities. Two scenarios are envisaged to explain the presence of H+-PPases in clade D, specifically placement of H+-PPase in clade D is an artifact of phylogenetic reconstitution, or the H+ specificity of some PPases in clade D is not homologous to that in clade A and K+-independent H+-PPases but a result of homoplasy. Our analysis of the Glu residues in TMH5 and TMH6 favors the latter possibility.The three subtypes of clade D membrane PPases are represented by Na+-transporting Cl-PPase, H+-transporting Fj-PPase, and plant-type H+-PPases. Cl-PPase is similar to enzymes from evolutionarily diverse bacteria. Fj-PPase has close homologs only in Bacteroidetes, whereas the plant category of H+-PPases additionally includes enzymes from unicellular protozoa and the spirochaete bacterium Leptospira. H+-transporting Fj-PPase and plant enzymes group polyphyletically and differ from all Na+-PPases and the clade D ancestor enzyme in that Glu242 (Cl-PPase numbering) is relocated from its cytoplasm-membrane interface position in TMH6 to a membrane-embedded position in TMH5 or TMH6, respectively. Several lines of evidence support the hypothesis that Glu242 relocations are key, albeit not the only structural modifications during the evolutionary pathways responsible for the H+ transport specificity of Fj-PPase-type and Leptospira/protozoan/plant-type enzymes. First, site-directed mutagenesis data indicate an essential role for TMH5 and TMH6 carboxyl groups in maintaining PPi hydrolysis coupling to H+ transport across the membrane. This conclusion is further supported by the recently published results of an alanine scanning mutagenesis study of transmembrane domain 6 of mung bean H+-PPase (40Pan Y.J. Lee C.H. Hsu S.H. Huang Y.T. Lee C.H. Liu T.H. Chen Y.W. Lin S.M. Pan R.L. Biochim. Biophys. Acta. 2011; 1807: 59-67Crossref PubMed Scopus (14) Google Scholar). Second, N,N′-dicyclohexylcarbodiimide, which preferentially reacts with protonated carboxyl groups, targets the relevant Glu residue in A. thaliana H+-PPase (AVP1) (41Zhen R.G. Kim E.J. Rea P.A. J. Biol. Chem. 1997; 272: 22340-22348Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). Finally, the E242D substitution leads to a dramatic increase in the Na+ concentration required for the maximal activity of Na+-PPase in the presence of K+, indicating changes in the affinity of the Na+-specific binding site that presumably functions as the cytoplasmic acceptor for the transported Na+ (42Malinen A.M. Baykov A.A. Lahti R. Biochemistry. 2008; 47: 13447-13454Crossref PubMed Scopus (17) Google Scholar).K+-independent enzymes from C. thermocellum and T. lettingae are phylogenetically the most closely related to K+-dependent PPases. Ct-PPase and Pa-PPase do not transport Na+ and may thus perform H+ transport activity similar to other characterized K+-independent membrane PPases, but this is yet to be directly demonstrated. Because five characterized K+-independent H+-PPases represent distinct divergent clades within the subfamily and no K+-independent Na+-PPases have been encountered so far, it is highly likely that all members of the K+-independent subfamily operate as H+ pumps.Significantly, the Na+-PPase and K+-independent H+-PPase genes are adjacent in the M. mazei genome, suggesting that the gene cluster is a footprint of an ancient gene duplication event resulting in the formation of the two deeply rooted subfamilies. To date, the classification of membrane PPases has been based on their requirement for K+. However, we speculate that the initial specialization of the duplicates leading to emergence of two subfamilies was, in fact, driven by changes in transported cation specificity and followed by secondary loss of K+ dependence in H+-PPases. Indeed, the absence of K+-independent Na+-PPases and our failure to generate such enzymes via mutagenesis 3G. A. Belogurov and H. H. Luoto, unpublished data. suggest that K+ independence is incompatible with Na+ pumping. The change in transport specificity adds to the capability of the organism to utilize PPi for the generation of both Na+ and H+ gradients, whereas changes in K+ dependence do not provide an immediate fitness benefit. We further propose that the ancestor enzyme is possibly a Na+ pump. Thus, the evolution of a membrane PPase coupling ion specificity from Na+ to H+ parallels the scenario suggested for Na+- and H+-coupled F- and V-type ATP synthases/ATPases and adds support to the concept of global evolutionary primacy of Na+-coupled bioenergetics (43Mulkidjanian A.Y. Galperin M.Y. Makarova K.S. Wolf Y.I. Koonin E.V. Biol. Direct. 2008; 3: 13Crossref PubMed Scopus (109) Google Scholar, 44Mulkidjanian A.Y. Dibrov P. Galperin M.Y. Biochim. Biophys. Acta. 2008; 1777: 985-992Crossref PubMed Scopus (116) Google Scholar, 45Mulkidjanian A.Y. Galperin M.Y. Koonin E.V. Trends Biochem. Sci. 2009; 34: 206-215Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 53Holm N.G. Baltscheffsky H. Orig. Life Evol. Biosph. April 2, 2011; 10.1007/s11084-011-9235-4PubMed Google Scholar).Further research is required to establish the physiological role of Na+-PPase. A literature search has revealed two interesting trends. First, Na+-PPase is more frequently found in anaerobic organisms than H+-PPase. Thus, 23 of the 30 characterized and predicted Na+-PPases in the phylogenetic tree (Fig. 1) are derived from anaerobic hosts, whereas only 14 of 49 H+-PPases belong to anaerobes. Thus, a change from an anaerobic to aerobic environment may have provided the driving force for evolution from PPi-energized Na+ pumping to H+ pumping. This is most evident in clade D, which contains four of seven aerobic Na+-PPases (compared with only 3 of 25 Na+-PPases from aerobic hosts in clades B and C). Second, at least half of the anaerobic and all except one of the aerobic Na+-PPase hosts are halophilic or halotolerant compared with only one-quarter of the H+-PPases. Accordingly, it is proposed that Na+-PPase function is related to creating salt tolerance, especially in aerobic host organisms. This theory may be extended to speculate that because Na+-PPase is naturally preferred in halophiles, this enzyme may prove better than H+-PPase (6Serrano A. Pérez-Castiñeira J.R. Baltscheffsky M. Baltscheffsky H. IUBMB Life. 2007; 59: 76-83Crossref PubMed Scopus (81) Google Scholar) in engineering salt tolerance in plants/microbes.In summary, our results confirm that a wide range of microorganisms employ PPi-energized Na+ extrusion systems. We provide a comprehensive reconstruction of membrane PPase evolution and predict the transport specificity of membrane PPases as follows: (i) K+-independent enzymes are proton pumps, (ii) K+-dependent enzymes belonging to clade N are sodium pumps if Glu is present at the TMH6 interface and proton pumps if the Glu residue is relocated, and (iii) K+-dependent enzymes belonging to clade A are proton pumps. Notably, the sequence determinants governing the differences in transport specificity between clades A and N are not fully clarified at present, and therefore, the position of the sequence in the phylogenetic tree is an essential part of the prediction algorithm. IntroductionMembrane pyrophosphatases (PPases 2The abbreviations used are: PPasepyrophosphataseCh-PPaseC. hydrogenoformans PPaseAc-PPaseA. caccae PPaseCl-PPaseC. limicola PPaseCt-PPaseC. thermocellum PPaseDa-PPaseD. acetoxidans PPaseFj-PPaseF. johnsoniae PPaseLb-PPaseL. biflexa PPasePa-PPaseP. aerophilum PPaseCtet-PPaseC. tetani PPaseTm-PPaseT. maritima PPaseIMVinner membrane vesicle(s)TMAtetramethylammoniumTMHtransmembrane helix.; EC 3.6.1.1; Transporter Classification Database number 3.A.10) couple the hydrolysis of PPi to the active transport of cations across membranes and display no sequence homology to any known protein family. Membrane PPases consist of 70–81-kDa subunits that apparently form a homodimer (1Maeshima M. Biochim. Biophys. Acta. 2000; 1465: 37-51Crossref PubMed Scopus (370) Google Scholar) and are divided into K+-dependent and K+-independent subfamilies. The key determinant of K+ dependence is a single amino acid position located near the cytoplasm-membrane interface, which is occupied by Ala in the K+-dependent and Lys in the K+-independent enzymes (2Belogurov G.A. Lahti R. J. Biol. Chem. 2002; 277: 49651-49654Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). All PPases additionally require Mg2+ for function (3Baykov A.A. Bakuleva N.P. Rea P.A. Eur. J. Biochem. 1993; 217: 755-762Crossref PubMed Scopus (65) Google Scholar).H+-transporting PPases (H+-PPases), discovered >40 years ago, are widespread among organisms in all three domains of life (4Baltscheffsky M. Nature. 1967; 216: 241-243Crossref PubMed Scopus (78) Google Scholar, 5Baltscheffsky H. Von Stedingk L.V. Heldt H.W. Klingenberg M. Science. 1966; 153: 1120-1122Crossref PubMed Scopus (141) Google Scholar, 6Serrano A. Pérez-Castiñeira J.R. Baltscheffsky M. Baltscheffsky H. IUBMB Life. 2007; 59: 76-83Crossref PubMed Scopus (81) Google Scholar). Both K+-dependent and K+-independent H+-PPases have been characterized. In bacteria and archaea, these enzymes generate an ion-motive force for ATP synthesis and transport processes, particularly during stress and low energy conditions (7Baltscheffsky M. Schultz A. Baltscheffsky H. FEBS Lett. 1999; 457: 527-533Crossref PubMed Scopus (108) Google Scholar, 8López-Marqués R.L. Pérez-Castiñeira J.R. Losada M. Serrano A. J. Bacteriol. 2004; 186: 5418-5426Crossref PubMed Scopus (40) Google Scholar, 9García-Contreras R. Celis H. Romero I. J. Bacteriol. 2004; 186: 6651-6655Crossref PubMed Scopus (25) Google Scholar). In eukaryotes, H+-PPase acts in parallel with H+-ATPase and plays important roles in securing acidity and thus the functionality of cellular organelles, such as vacuoles in plants (1Maeshima M. Biochim. Biophys. Acta. 2000; 1465: 37-51Crossref PubMed Scopus (370) Google Scholar, 6Serrano A. Pérez-Castiñeira J.R. Baltscheffsky M. Baltscheffsky H. IUBMB Life. 2007; 59: 76-83Crossref PubMed Scopus (81) Google Scholar, 10Drozdowicz Y.M. Rea P.A. Trends Plant Sci. 2001; 6: 206-211Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar) and acidocalcisomes in protozoa (11Docampo R. de Souza W. Miranda K. Rohloff P. Moreno S.N. Nat. Rev. Microbiol. 2005; 3: 251-261Crossref PubMed Scopus (344) Google Scholar). In plants, H+-PPase appears to be involved in auxin-dependent organ development (12Fukuda A. Tanaka Y. Plant Physiol. Biochem. 2006; 44: 351-358Crossref PubMed Scopus (61) Google Scholar, 13Li J. Yang H. Peer W.A. Richter G. Blakeslee J. Bandyopadhyay A. Titapiwantakun B. Undurraga S. Khodakovskaya M. Richards E.L. Krizek B. Murphy A.S. Gilroy S. Gaxiola R. Science. 2005; 310: 121-125Crossref PubMed Scopus (339) Google Scholar), and overexpression of the pump in agricultural plants confers resistance against water/nutrient deprivation, cold, and salinity (14Zhang J. Li J. Wang X. Chen J. Plant Physiol. Biochem. 2011; 49: 33-38Crossref PubMed Scopus (51) Google Scholar, 15Lv S. Zhang K. Gao Q. Lian L. Song Y. Zhang J. Plant Cell Physiol. 2008; 49: 1150-1164Crossref PubMed Scopus (139) Google Scholar, 16Li B. Wei A. Song C. Li N. Zhang J. Plant Biotechnol. J. 2008; 6: 146-159Crossref PubMed Scopus (100) Google Scholar, 17Park S. Li J. Pittman J.K. Berkowitz G.A. Yang H. Undurraga S. Morris J. Hirschi K.D. Gaxiola R.A. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 18830-18835Crossref PubMed Scopus (222) Google Scholar). Furthermore, H+-PPase is a promising drug target in protozoan parasites (18Docampo R. Moreno S.N. Curr. Pharm. Des. 2008; 14: 882-888Crossref PubMed Scopus (58) Google Scholar).In contrast, Na+-transporting PPases (Na+-PPases) were only recently identified in the mesophilic archaeon Methanosarcina mazei, the moderately thermophilic acetogenic bacterium Moorella thermoacetica, and the marine hyperthermophilic bacterium Thermotoga maritima (19Malinen A.M. Belogurov G.A. Baykov A.A. Lahti R. Biochemistry. 2007; 46: 8872-8878Crossref PubMed Scopus (47) Google Scholar). These enzymes are similar to the H+-PPases in many aspects but require both K+ and Na+ for activity (20Belogurov G.A. Malinen A.M. Turkina M.V. Jalonen U. Rytkönen K. Baykov A.A. Lahti R. Biochemistry. 2005; 44: 2088-2096Crossref PubMed Scopus (26) Google Scholar).The initial discovery of Na+-PPases in the contrasting ecological and evolutionary niches suggests that PPi-energized Na+ transport is a ubiquitous process. However, verification of this hypothesis has been severely hampered by our inability to predict transport specificity directly from protein sequence information. In this study, we overcame this limitation by experimentally screening transport specificity across different types of membrane PPases. These data, in conjugation with phylogenetic analysis, indicate that Na+ transport specificity is indeed a very common property and preceded H+ transport specificity in the evolutionary history of the protein family. We additionally employed site-directed mutagenesis to identify the structural elements defining membrane PPase transport specificity." @default.
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• W1987482305 title "Na+-translocating Membrane Pyrophosphatases Are Widespread in the Microbial World and Evolutionarily Precede H+-translocating Pyrophosphatases" @default.
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• W1987482305 doi "https://doi.org/10.1074/jbc.m111.244483" @default.
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