The functions of metamorphic metallothioneins in zinc and copper metabolism

Recent discoveries in zinc biology provide a new platform for discussing the primary physiological functions of mammalian metallothioneins (MTs) and their exquisite zinc-dependent regulation. It is now understood that the control of cellular zinc homeostasis includes buffering of Zn2+ ions at picomolar concentrations, extensive subcellular re-distribution of Zn2+, the loading of exocytotic vesicles with zinc species, and the control of Zn2+ ion signalling. In parallel, characteristic features of human MTs became known: their graded affinities for Zn2+ and the redox activity of their thiolate coordination environments. Unlike the single species that structural models of mammalian MTs describe with a set of seven divalent or eight to twelve monovalent metal ions, MTs are metamorphic. In vivo, they exist as many species differing in redox state and load with different metal ions. The functions of mammalian MTs should no longer be considered elusive or enigmatic because it is now evident that the reactivity and coordination dynamics of MTs with Zn2+ and Cu+ match the biological requirements for controlling—binding and delivering—these cellular metal ions, thus completing a 60-year search for their functions. MT represents a unique biological principle for buffering the most competitive essential metal ions Zn2+ and Cu+. How this knowledge translates to the function of other families of MTs awaits further insights into the specifics of how their properties relate to zinc and copper metabolism in other organisms

Self-organized defect strings in two-dimensional crystals

Using experiments with single particle resolution and computer simulations we study the collective behaviour of multiple vacancies injected into two-dimensional crystals. We find that the defects assemble into linear strings that propagate through the crystal in a succession of rapid one-dimensional gliding phases and rare rotations, during which the direction of motion changes. At both ends, strings are terminated by dislocations with anti-parallel Burgers vectors. By monitoring the separation of the dislocations, we measure their effective interactions with high precision, for the first time beyond spontaneous formation and annihilation, and explain the double-well form of the dislocation interaction in terms of continuum elasticity theory. Our results give a detailed picture of the motion and interaction of dislocations in two dimensions and enhance our understanding of topological defects in two-dimensional nano-materials

Entropy and Kinetics of Point-Defects in Two-Dimensional Dipolar Crystals

We study in experiment and with computer simulation the free energy and the kinetics of vacancy and interstitial defects in two-dimensional dipolar crystals. The defects appear in different local topologies which we characterize by their point group symmetry; $C_n$ is the n-fold cyclic group and $D_n$ is the dihedral group, including reflections. The frequency of different local topologies is not determined by their almost degenerate energies but dominated by entropy for symmetric configurations. The kinetics of the defects is fully reproduced by a master equation in a multi-state Markov model. In this model, the system is described by the state of the defect and the time evolution is given by transitions occurring with particular rates. These transition rate constants are extracted from experiments and simulations using an optimisation procedure. The good agreement between experiment, simulation and master equation thus provides evidence for the accuracy of the model.Comment: 9 pages, 12 figure

Bert Vallee—A 20th Century Adventure(r) in Zincology

Prelude [...

Role of zinc and magnesium ions in the modulation of phosphoryl transfer in protein tyrosine phosphatase 1B

While the majority of phosphatases are metalloenzymes, the prevailing model for the reactions catalyzed by protein tyrosine phosphatases does not involve any metal ion, yet both metal cations and oxoanions affect their enzymatic activity. Mg2+ and Zn2+ activate and inhibit, respectively, protein tyrosine phosphatase 1B (PTP1B). Molecular dynamics simulations, metadynamics, and quantum chemical calculations in combination with experimental investigations demonstrate that Mg2+ and Zn2+ compete for the same binding site in the active site only in the closed conformation of the enzyme in its phosphorylated state. The two cations have different effects on the arrangements and activities of water molecules that are necessary for the hydrolysis of the phosphocysteine intermediate in the second catalytic step of the reaction. Remarkable differences between the established structural enzymology of PTP1B investigated ex vivo and the function of PTP1B in vivo become evident. Different reaction pathways are viable when the presence of metal ions and their cellular concentrations are considered. The findings suggest that the substrate delivers the inhibitory Zn2+ ion to the active site. The inhibition and activation can be ascribed to the different coordination chemistries of Zn2+ and Mg2+ ions and the orientation of the metal-coordinated water molecules. Metallochemistry adds an additional dimension to the regulation of PTP1B and presumably other members of this enzyme family

Obesity, diabetes and zinc: A workshop promoting knowledge and collaboration between the UK and Israel, November 28–30, 2016 – Israel

Sponsored by the Friends of Israel Educational Foundation (FIEF) and Ben-Gurion University of the Negev and supported by the EU COST action Zinc-Net (COST TD1304), a three-day collaborative UK-Israel workshop was organized by Drs Assaf Rudich, Imre Lengyel and Arie Moran. Participants from the UK and Israel met at the Desert Iris Hotel, Yeruham, Israel between the 28-30th of November 2016 for in-depth discussions, rather than a lecture series, to set the stage for future collaborative grants and projects on diabetes and zinc. Two days of formal scientific sessions with dynamic and wide-ranging discussions was followed by a day of touring and informal networking in the Negev area. This format was previously recognized by our sponsors as both effective and enjoyable and all participants agreed at the end of the meeting that the 3-days provided an excellent basis for future scientific collaboration. The discussions were centered on diabetes and obesity, already at pandemic levels, and zinc homeostasis which is related to the clinical issues and themes of the meeting. The free-flowing discussions were based on short presentations setting the scene for the six main topics: ‘Diabetes and zinc transporters’, ‘Nutrition related factors’, ‘Biomarkers’, ‘Clinical epidemiology’, ‘the Microbiome and diabetes’, and ‘Related diseases’. The abstract style summary of the sessions is followed by the major discussion points raised by the Authors and other participants (UK: Patrik Rorsman, Oxford University; Alan Stewart, University of St Andrews and Israel: Assaf Rudich, Idit Liberty, Rahel Gol, Guy Las and Amos Katz, Ben-Gurion University; Sarah Zangen, Haddassa University). We hope that readers will find this discourse stimulating and some of the ideas might make their way into their research efforts

Versatile strategy for homogeneous drying patterns of dispersed particles

After spilling coffee, a tell-tale stain is left by the drying droplet. This universal phenomenon, known as the coffee ring effect, is observed independent of the dispersed material. However, for many technological processes such as coating techniques and ink-jet printing a uniform particle deposition is required and the coffee ring effect is a major drawback. Here, we present a simple and versatile strategy to achieve homogeneous drying patterns using surface-modified particle dispersions. High-molecular weight surface-active polymers that physisorb onto the particle surfaces provide enhanced steric stabilization and prevent accumulation and pinning at the droplet edge. In addition, in the absence of free polymer in the dispersion, the surface modification strongly enhances the particle adsorption to the air/liquid interface, where they experience a thermal Marangoni backflow towards the apex of the drop, leading to uniform particle deposition after drying. The method is independent of particle shape and applicable to a variety of commercial pigment particles and different dispersion media, demonstrating the practicality of this work for everyday processes

The ZIP6/ZIP10 heteromer is essential for the zinc-mediated trigger of mitosis

Zinc has been known to be essential for cell division for over 40 years but the molecular pathways involved remain elusive. Cellular zinc import across biological membranes necessitates the help of zinc transporters such as the SLC39A family of ZIP transporters. We have discovered a molecular process that explains why zinc is required for cell division, involving two highly regulated zinc transporters, as a heteromer of ZIP6 and ZIP10, providing the means of cellular zinc entry at a specific time of the cell cycle that initiates a pathway resulting in the onset of mitosis. Crucially, when the zinc influx across this heteromer is blocked by ZIP6 or ZIP10 specific antibodies, there is no evidence of mitosis, confirming the requirement for zinc influx as a trigger of mitosis. The zinc that influxes into cells to trigger mitosis additionally changes the phosphorylation state of STAT3 converting it from a transcription factor to a protein that complexes with this heteromer and pS38Stathmin, the form allowing microtubule rearrangement as required in mitosis. This discovery now explains the specific cellular role of ZIP6 and ZIP10 and how they have special importance in the mitosis process compared to other ZIP transporter family members. This finding offers new therapeutic opportunities for inhibition of cell division in the many proliferative diseases that exist, such as cancer