Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022716 (Menkes)
 1,057 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human copper-ATPases ATP7A and ATP7B are essential for intracellular copper homeostasis. The main roles of the Menkes protein, ATP7A, are the delivery of copper to the secretory pathway and the export of excess copper from the enterocytes. The N-terminal domain of membrane protein ATP7A consists of six repetitive sequences of 60-70 amino acids (Mnk1-Mnk6) that fold into individual metal binding domains (MBDs) and bind a single copper ion in the reduced Cu(I) form via two cysteine residues. The structure of each individual MBD is known from nuclear magnetic resonance experiments. Here, we were interested in the stability and dynamics of each isolated MBD in their apo and holo forms and their interactions with the soluble metallochaperone HAH1 that delivers copper to ATP7A. Using molecular dynamics simulations of the MBDs under different conditions, we show that some MBDs (Mnk1 and Mnk5) present large root-mean-square deviations from initial structures or large root-mean-square fluctuations, and great care has to be taken in setting up the simulations. We propose that the first MBD, Mnk1, probably important in the transfer of copper between the metallochaperone and ATPase, could be stabilized by interactions with other MBDs, including a domain located in the loop between Mnk1 and Mnk2. An important result of this work is the apparent direct correlation between the difference in the fluctuations of the metal binding site loop in its apo and holo forms and the measured affinity of the MBD for copper. This difference decreases from Mnk1 to Mnk6, Mnk4, and Mnk2 in this order. The study of the exposure to the solvent of the metal and the residues of the metal binding loop of the MBDs also shows different behavior for each MBD. In particular, copper in serine-rich domain Mnk3 and largely fluctuating domain Mnk5 appears to be more solvent-exposed than in the other MBDs. In the second part of this work, we investigated the importance of electrostatics in the MBD-chaperone interactions using different docking programs. Mnk1 and Mnk4 present a large electrostatic dipole moment and large stabilizing interaction energies with HAH1. Finally, we propose a model structure of ATP7A from Mnk6 (E561) to P1413 based on the crystal structure of LpCopA and docking simulations.
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PMID:Dynamics and stability of the metal binding domains of the Menkes ATPase and their interaction with metallochaperone HAH1. 2307 77

The kinases Mnk1 and Mnk2 are activated downstream of the p38 MAPK and MEK/ERK signaling pathways. Extensive work over the years has shown that these kinases control phosphorylation of the eukaryotic initiation factor 4E (eIF4E) and regulate engagement of other effector elements, including hnRNPA1 and PSF. Mnk kinases are ubiquitously expressed and play critical roles in signaling for various cytokine receptors, while there is emerging evidence that they have important functions as mediators of pro-inflammatory cytokine production. In this review the mechanisms of activation of MNK pathways by cytokine receptors are addressed and their roles in diverse cytokine-dependent biological processes are reviewed. The clinical-translational implications of such work and the relevance of future development of specific MNK inhibitors for the treatment of malignancies and auto-immune disorders are discussed.
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PMID:Mnk Kinases in Cytokine Signaling and Regulation of Cytokine Responses. 2371 Feb 61

Copper (Cu) is required for maturation of cuproenzymes, cell proliferation, and angiogenesis, and its transport entails highly specific protein-protein interactions. In humans, the Cu chaperone Atox1 mediates Cu(I) delivery to P-type ATPases Atp7a and Atp7b (the Menkes and Wilson disease proteins, respectively), which are responsible for Cu release to the secretory pathway and excess Cu efflux. Cu(I) handover is believed to occur through the formation of three-coordinate intermediates where the metal ion is simultaneously linked to Atox1 and to a soluble domain of Cu-ATPases, both sharing a CxxC dithiol motif. The ultrahigh thermodynamic stability of chelating S-donor ligands secures the redox-active and potentially toxic Cu(I) ion, while their kinetic lability allows facile metal transfer. The same CxxC motifs can interact with and mediate the biological response to antitumor platinum drugs, which are among the most used chemotherapeutics. We show that cisplatin and an oxaliplatin analogue can specifically bind to the heterodimeric complex Atox1-Cu(I)-Mnk1 (Mnk1 is the first soluble domain of Atp7a), thus leading to a kinetically stable adduct that has been structurally characterized by solution NMR and X-ray crystallography. Of the two possible binding configurations of the Cu(I) ion in the cage made by the CxxC motifs of the two proteins, one (bidentate Atox1 and monodentate Mnk1) is less stable and more reactive toward cis-Pt(II) compounds, as shown by using mutated proteins. A Cu(I) ion can be retained at the Pt(II) coordination site but can be released to glutathione (a physiological thiol) or to other complexing agents. The Pt(II)-supported heterodimeric complex does not form if Zn(II) is used in place of Cu(I) and transplatin instead of cisplatin. The results indicate that Pt(II) drugs can specifically affect Cu(I) homeostasis by interfering with the rapid exchange of Cu(I) between Atox1 and Cu-ATPases with consequences on cancer cell viability and migration.
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PMID:Mechanistic and Structural Basis for Inhibition of Copper Trafficking by Platinum Anticancer Drugs. 3128 25