Na+,K+-ATPase as a docking station: protein–protein complexes of the Na+,K+-ATPase

Reinhard, Linda; Tidow, Henning; Clausen, Michael V.; Nissen, Poul

doi:10.1007/s00018-012-1039-9

Cited by 126 publications

(137 citation statements)

References 153 publications

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“…determined, it has been suggested to take the place of NAKβ, and accordingly, it is reasonable to consider that agrin and NAKβ share the same binding region (59). Taken together, these observations suggest that peptidomimetics would not disrupt interactions between NAKα3 and proteins other than ASPD.…”

Section: Discussionmentioning

confidence: 88%

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Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly

Ohnishi

Yanazawa

Sasahara

et al. 2015

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

119

155

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Neurodegeneration correlates with Alzheimer's disease (AD) symptoms, but the molecular identities of pathogenic amyloid β-protein (Aβ) oligomers and their targets, leading to neurodegeneration, remain unclear. Amylospheroids (ASPD) are AD patient-derived 10-to 15-nm spherical Aβ oligomers that cause selective degeneration of mature neurons. Here, we show that the ASPD target is neuronspecific Na + /K + -ATPase α3 subunit (NAKα3). ASPD-binding to NAKα3 impaired NAKα3-specific activity, activated N-type voltage-gated calcium channels, and caused mitochondrial calcium dyshomeostasis, tau abnormalities, and neurodegeneration. NMR and molecular modeling studies suggested that spherical ASPD contain N-terminal-Aβ-derived "thorns" responsible for target binding, which are distinct from low molecular-weight oligomers and dodecamers. The fourth extracellular loop (Ex4) region of NAKα3 encompassing Asn 879 and Trp 880 is essential for ASPD-NAKα3 interaction, because tetrapeptides mimicking this Ex4 region bound to the ASPD surface and blocked ASPD neurotoxicity. Our findings open up new possibilities for knowledge-based design of peptidomimetics that inhibit neurodegeneration in AD by blocking aberrant ASPD-NAKα3 interaction.NMR | computational modeling | abnormal protein-protein interaction in synapse | hyperexcitotoxicity | protein-protein interaction inhibitors

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Section: Discussionmentioning

confidence: 88%

“…Except for the NAKβ subunit and agrin, all other NAKα-binding proteins have been reported to bind to the intracellular region of NAKα (59). Because this NAKβ-binding region is located 10 amino acids more C-terminally than Trp 880 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly

Ohnishi

Yanazawa

Sasahara

et al. 2015

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

119

155

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“…ATP1A1 is the catalytic subunit of Na + ,K + -ATPase, an ion pump that also plays a role in signal transduction when inhibited by ouabain (Reinhard et al, 2013), making it a candidate therapeutic target for diseases such as medulloblastoma (Wolle et al, 2014). MAPK1 26, 2017; phosphorylates ATP1A1 in response to insulin (Al-Khalili et al, 2004) and proinsulinconnecting peptide (C-peptide) (Zhong et al, 2004) stimulation, potentially on T81.…”

Section: Role Of Novel Tested Egfr Pathway Edgesmentioning

confidence: 99%

Synthesizing Signaling Pathways from Temporal Phosphoproteomic Data

Köksal

Beck

Cronin

et al. 2017

Preprint

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Advances in proteomics reveal that pathway databases fail to capture the majority of cellular signaling activity. Our mass spectrometry study of the dynamic epidermal growth factor (EGF) response demonstrates that over 89% of significantly (de)phosphorylated proteins are excluded from individual EGF signaling maps, and 63% are absent from all annotated pathways. We present a computational method, the Temporal Pathway Synthesizer (TPS), to discover missing pathway elements by modeling temporal phosphoproteomic data. TPS uses constraint solving to exhaustively explore all possible structures for a signaling pathway, eliminating structures that are inconsistent with protein-protein interactions or the observed phosphorylation event timing. Applied to our EGF response data, TPS connects 83% of the responding proteins to receptors and signaling proteins in EGF pathway maps. Inhibiting predicted active kinases supports the TPS pathway model. The TPS algorithm is broadly applicable and also recovers an accurate model of the yeast osmotic stress response.

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“…This gradient also drives amino acids and vitamin transport into cells [4]. Beside this, the electrochemical gradient is essential for physiological processes such as electrical excitability, nerve transmission, and muscle contraction [5,6]. The transport of Na + and K + is accomplished by conformational changes.…”

Section: Introductionmentioning

confidence: 99%

Na,K-ATPase reconstituted in ternary liposome: The presence of cholesterol affects protein activity and thermal stability

Yoneda

Rigos

Lourenço

et al. 2014

Archives of Biochemistry and Biophysics

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Differential scanning calorimetry (DSC) was applied to investigate the effect of cholesterol on the thermotropic properties of the lipid membrane (DPPC and DPPE). The thermostability and unfolding of solubilized and reconstituted Na,K-ATPase in DPPC:DPPE:cholesterol-liposomes was also studied to gain insight into the role of cholesterol in the Na,K-ATPase modulation of enzyme function and activity. The tertiary system (DPPC:DPPE:cholesterol) (molar ratio DPPC:DPPE equal 1:1) when cholesterol content was increased from 0% up to 40% results in a slight decrease in the temperature of transition and enthalpy, and an increase in width. We observed that, without heating treatment, at 37°C, the activity was higher for 20mol% cholesterol. However, thermal inactivation experiments showed that the enzyme activity loss time depends on the cholesterol membrane content. The unfolding of the enzyme incorporated to liposomes of DPPC:DPPE (1:1mol) with different cholesterol contents, ranging from 0% to 40% mol was also studied by DSC. Some differences between the thermograms indicate that the presence of lipids promotes a conformational change in protein structure and this change is enough to change the way Na,K-ATPase thermally unfolds.

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Na+,K+-ATPase as a docking station: protein–protein complexes of the Na+,K+-ATPase

Cited by 126 publications

References 153 publications

Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly

Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly

Synthesizing Signaling Pathways from Temporal Phosphoproteomic Data

Na,K-ATPase reconstituted in ternary liposome: The presence of cholesterol affects protein activity and thermal stability

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