P-type ATPases at a glance

Bublitz, Maike; Morth, J. Preben; Nissen, Poul

doi:10.1242/jcs.088716

Cited by 132 publications

(96 citation statements)

References 69 publications

(59 reference statements)

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“…Based on crystallographic and functional evidence, NKA displays three domains, the N-terminal actuator (A) domain from aa 1-288 that includes the first intracellular loop (ICL1), and is followed by the catalytic center with the nucleotide (N) binding and the phosphorylation (P) domains in ICL2 [55,56]. …”

Section: Resultsmentioning

confidence: 99%

Canonical Bcl-2 Motifs of the Na+/K+ Pump Revealed by the BH3 Mimetic Chelerythrine: Early Signal Transducers of Apoptosis?

Lauf

Heiny

Meller

et al. 2013

Cell Physiol Biochem

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Background/Aims: Chelerythrine [CET], a protein kinase C [PKC] inhibitor, is a prop-apoptotic BH3-mimetic binding to BH1-like motifs of Bcl-2 proteins. CET action was examined on PKC phosphorylation-dependent membrane transporters (Na⁺/K⁺ pump/ATPase [NKP, NKA], Na⁺-K⁺-2Cl⁺ [NKCC] and K⁺-Cl^- [KCC] cotransporters, and channel-supported K⁺ loss) in human lens epithelial cells [LECs]. Methods: K⁺ loss and K⁺ uptake, using Rb⁺ as congener, were measured by atomic absorption/emission spectrophotometry with NKP and NKCC inhibitors, and Cl^- replacement by NO₃^ˉ to determine KCC. ³H-Ouabain binding was performed on a pig renal NKA in the presence and absence of CET. Bcl-2 protein and NKA sequences were aligned and motifs identified and mapped using PROSITE in conjunction with BLAST alignments and analysis of conservation and structural similarity based on prediction of secondary and crystal structures. Results: CET inhibited NKP and NKCC by >90% (IC₅₀ values ∼35 and ∼15 µM, respectively) without significant KCC activity change, and stimulated K⁺ loss by ∼35% at 10-30 µM. Neither ATP levels nor phosphorylation of the NKA α1 subunit changed. ³H-ouabain was displaced from pig renal NKA only at 100 fold higher CET concentrations than the ligand. Sequence alignments of NKA with BH1- and BH3-like motifs containing pro-survival Bcl-2 and BclXl proteins showed more than one BH1-like motif within NKA for interaction with CET or with BH3 motifs. One NKA BH1-like motif (ARAAEILARDGPN) was also found in all P-type ATPases. Also, NKA possessed a second motif similar to that near the BH3 region of Bcl-2. Conclusion: Findings support the hypothesis that CET inhibits NKP by binding to BH1-like motifs and disrupting the α₁ subunit catalytic activity through conformational changes. By interacting with Bcl-2 proteins through their complementary BH1- or BH3-like-motifs, NKP proteins may be sensors of normal and pathological cell functions, becoming important yet unrecognized signal transducers in the initial phases of apoptosis. CET action on NKCC1 and K⁺ channels may involve PKC-regulated mechanisms; however, limited sequence homologies to BH1-like motifs cannot exclude direct effects.

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Section: Resultsmentioning

confidence: 99%

Canonical Bcl-2 Motifs of the Na+/K+ Pump Revealed by the BH3 Mimetic Chelerythrine: Early Signal Transducers of Apoptosis?

Lauf

Heiny

Meller

et al. 2013

Cell Physiol Biochem

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“…4b). This assembly contradicts our basic understanding of P-type ATPases (Bublitz et al, 2011). Ca of Ca 2+ -ATPases are always located on the cytoplasmic face of the membrane.…”

Section: Misannotated Oligomers Deviate From Power-law Behaviormentioning

confidence: 86%

Empirical power laws for the radii of gyration of protein oligomers

Tanner

2016

Acta Crystallogr D Struct Biol

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The radius of gyration is a fundamental structural parameter that is particularly useful for describing polymers. It has been known since Flory's seminal work in the mid-20th century that polymers show a power-law dependence, where the radius of gyration is proportional to the number of residues raised to a power. The power-law exponent has been measured experimentally for denatured proteins and derived empirically for folded monomeric proteins using crystal structures. Here, the biological assemblies in the Protein Data Bank are surveyed to derive the power-law parameters for protein oligomers having degrees of oligomerization of 2–6 and 8. The power-law exponents for oligomers span a narrow range of 0.38–0.41, which is close to the value of 0.40 obtained for monomers. This result shows that protein oligomers exhibit essentially the same power-law behavior as monomers. A simple power-law formula is provided for estimating the oligomeric state from an experimental measurement of the radius of gyration. Several proteins in the Protein Data Bank are found to deviate substantially from power-law behavior by having an atypically large radius of gyration. Some of the outliers have highly elongated structures, such as coiled coils. For coiled coils, the radius of gyration does not follow a power law and instead scales linearly with the number of residues in the oligomer. Other outliers are proteins whose oligomeric state or quaternary structure is incorrectly annotated in the Protein Data Bank. The power laws could be used to identify such errors and help prevent them in future depositions.

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“…Moreover, pH i variations could be a trigger signal or constitute an optimal intracellular environment for proliferation, dimorphic switching, and virulence of pathogenic yeasts (5; reviewed in reference 6). Finally, pH i decrease is an early apoptotic event observed in yeast and in the death receptor-mediated and mitochondrion-dependent apoptosis of higher eukaryotic cells (7,8,9; reviewed in reference 10).The plasma membrane protein Pma1p (P 3A -type ATPase) is a single catalytic polypeptide (ϳ100 kDa) that couples ATP hydrolysis to the expulsion of protons, generating an electrochemical proton gradient necessary for nutrient uptake and cellular ion balance (11,12,13,14,15,16). This H ϩ -ATPase is a primary contributor to pH i regulation and is crucial for cell survival, as shown by the potent fungicidal activity of certain Pma1p inhibitors.…”

mentioning

confidence: 99%

“…The plasma membrane protein Pma1p (P 3A -type ATPase) is a single catalytic polypeptide (ϳ100 kDa) that couples ATP hydrolysis to the expulsion of protons, generating an electrochemical proton gradient necessary for nutrient uptake and cellular ion balance (11,12,13,14,15,16). This H ϩ -ATPase is a primary contributor to pH i regulation and is crucial for cell survival, as shown by the potent fungicidal activity of certain Pma1p inhibitors.…”

mentioning

confidence: 99%

Antifungal Mechanism of Action of Lactoferrin: Identification of H ⁺ -ATPase (P _3A -Type) as a New Apoptotic-Cell Membrane Receptor

Andrés

Acosta-Zaldívar

Fierro

2016

Antimicrob Agents Chemother

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bHuman lactoferrin (hLf) is a protein of the innate immune system which induces an apoptotic-like process in yeast. Determination of the susceptibility to lactoferrin of several yeast species under different metabolic conditions, respiratory activity, cytoplasmic ATP levels, and external medium acidification mediated by glucose assays suggested plasma membrane Pma1p (P 3A -type ATPase) as the hLf molecular target. The inhibition of plasma membrane ATPase activity by hLf and the identification of Pma1p as the hLf-binding membrane protein confirmed the previous physiological evidence. Consistent with this, cytoplasmic ATP levels progressively increased in hLf-treated Candida albicans cells. However, oligomycin, a specific inhibitor of the mitochondrial F-type ATPase proton pump (mtATPase), abrogated the antifungal activity of hLf, indicating a crucial role for mtATPase in the apoptotic process. We suggest that lactoferrin targeted plasma membrane Pma1p H ؉ -ATPase, perturbing the cytoplasmic ion homeostasis (i.e., cytoplasmic H ؉ accumulation and subsequent K ؉ efflux) and inducing a lethal mitochondrial dysfunction. This initial event involved a normal mitochondrial ATP synthase activity responsible for both the ATP increment and subsequent hypothetical mitochondrial proton flooding process. We conclude that human lactoferrin inhibited Pma1p H ؉ -ATPase, inducing an apoptotic-like process in metabolically active yeast. Involvement of mitochondrial H ؉ -ATPase (nonreverted) was essential for the progress of this programmed cell death in which the ionic homeostasis perturbation seems to precede classical nonionic apoptotic events. L actoferrin (Lf) is a 77-kDa iron-binding glycoprotein of the transferrin family of proteins and an important effector molecule of innate immunity with antimicrobial activity in mammalian mucosal fluids (reviewed in reference 1). We have previously reported that human lactoferrin (hLf) induces apoptosis-like cell death of the pathogenic opportunistic yeast pathogen Candida albicans, demonstrating also that K ϩ channel-mediated K ϩ efflux is a common apoptotic event in yeast and metazoan cells (2). At present, the mechanism of action by which lactoferrin and other antimicrobial peptides induce apoptosis-like processes in yeast remains unknown (reviewed in reference 3). However, we have previously identified in bacteria the proton-translocating ATPase (H ϩ -ATPase) as the molecular target of lactoferrin, suggesting that the subsequent perturbation of the proton gradient (⌬pH) and intracellular pH (pH i ) will lead to cell death in vitro (4). This finding revealed lactoferrin as a natural extracellular inhibitor of the proton translocation mediated by H ϩ -ATPases, suggesting that the possible inhibition of a similar target also explains its antifungal activity. In this hypothetical case, the antifungal effect of lactoferrin might be due to altered pH homeostasis, as reported for bacteria (4).In yeast, control of pH i is critical for cell survival and is regulated through a concerted moveme...

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P-type ATPases at a glance

Cited by 132 publications

References 69 publications

Canonical Bcl-2 Motifs of the Na<sup>+</sup>/K<sup>+</sup> Pump Revealed by the BH3 Mimetic Chelerythrine: Early Signal Transducers of Apoptosis?

Canonical Bcl-2 Motifs of the Na<sup>+</sup>/K<sup>+</sup> Pump Revealed by the BH3 Mimetic Chelerythrine: Early Signal Transducers of Apoptosis?

Empirical power laws for the radii of gyration of protein oligomers

Antifungal Mechanism of Action of Lactoferrin: Identification of H ⁺ -ATPase (P _3A -Type) as a New Apoptotic-Cell Membrane Receptor

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P-type ATPases at a glance

Cited by 132 publications

References 69 publications

Canonical Bcl-2 Motifs of the Na<sup>+</sup>/K<sup>+</sup> Pump Revealed by the BH3 Mimetic Chelerythrine: Early Signal Transducers of Apoptosis?

Canonical Bcl-2 Motifs of the Na<sup>+</sup>/K<sup>+</sup> Pump Revealed by the BH3 Mimetic Chelerythrine: Early Signal Transducers of Apoptosis?

Empirical power laws for the radii of gyration of protein oligomers

Antifungal Mechanism of Action of Lactoferrin: Identification of H + -ATPase (P 3A -Type) as a New Apoptotic-Cell Membrane Receptor

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Antifungal Mechanism of Action of Lactoferrin: Identification of H ⁺ -ATPase (P _3A -Type) as a New Apoptotic-Cell Membrane Receptor