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Salbreux G.,Max Planck Institute for the Physics of Complex Systems | Charras G.,London Center for Nanotechnology | Charras G.,University College London | Paluch E.,Max Planck Institute of Molecular Cell Biology and Genetics | Paluch E.,International Institute of Molecular and Cell Biology
Trends in Cell Biology

The cortex is a thin, crosslinked actin network lying immediately beneath the plasma membrane of animal cells. Myosin motors exert contractile forces in the meshwork. Because the cortex is attached to the cell membrane, it plays a central role in cell shape control. The proteic constituents of the cortex undergo rapid turnover, making the cortex both mechanically rigid and highly plastic, two properties essential to its function. The cortex has recently attracted increasing attention and its functions in cellular processes such as cytokinesis, cell migration, and embryogenesis are progressively being dissected. In this review, we summarize current knowledge on the structural organization, composition, and mechanics of the actin cortex, focusing on the link between molecular processes and macroscopic physical properties. We also highlight consequences of cortex dysfunction in disease. © 2012. Source

Wisniewska M.B.,International Institute of Molecular and Cell Biology | Wisniewska M.B.,University of Warsaw
Neurochemical Research

Wnt/β-catenin pathway, the effectors of which are transcription factors of the LEF1/TCF family, is primarily associated with development. Strikingly, however, some of the genes of the pathway are schizophrenia susceptibility genes, and the proteins that are often mutated in neurodegenerative diseases have the ability to regulate β-catenin levels. If impairment of this pathway indeed leads to these pathologies, then it likely plays a physiological role in the adult brain. This review provides an overview of the current knowledge on this subject. The involvement of β-catenin and LEF1/TCF factors in adult neurogenesis, synaptic plasticity, and the function of thalamic neurons are discussed. The data are still very preliminary and often based on circumstantial or indirect evidence. Further research might help to understand the etiology of the aforementioned pathologies. © 2013 The Author(s). Source

Green R.A.,Ludwig Institute for Cancer Research | Paluch E.,Max Planck Institute of Molecular Cell Biology and Genetics | Paluch E.,International Institute of Molecular and Cell Biology | Oegema K.,Ludwig Institute for Cancer Research
Annual Review of Cell and Developmental Biology

Cytokinesis, the final step in cell division, partitions the contents of a single cell into two. In animal cells, cytokinesis occurs through cortical remodeling orchestrated by the anaphase spindle. Cytokinesis relies on a tight interplay between signaling and cellular mechanics and has attracted the attention of both biologists and physicists for more than a century. In this review, we provide an overview of four topics in animal cell cytokinesis: (a) signaling between the anaphase spindle and cortex, (b) the mechanics of cortical remodeling, (c) abscission, and (d) regulation of cytokinesis by the cell cycle machinery. We report on recent progress in these areas and highlight some of the outstanding questions that these findings bring into focus. Copyright © 2012 by Annual Reviews. All rights reserved. Source

Miaczynska M.,International Institute of Molecular and Cell Biology
Cold Spring Harbor Perspectives in Biology

The intracellular trafficking machinery contributes to the spatial and temporal control of signaling by receptor tyrosine kinases (RTKs). The primary role in this process is played by endocytic trafficking, which regulates the localization of RTKs and their downstream effectors, aswell as the duration and the extent of their activity. The key regulatory points along the endocytic pathway are internalization of RTKs from the plasma membrane, their sorting to degradation or recycling, and their residence in various endosomal compartments. Here I will review factors and mechanisms that modulate RTK signaling by (1) affecting receptor internalization, (2) regulating the balance between degradation and recycling of RTK, and (3) compartmentalization of signals in endosomes and other organelles. Cumulatively, these mechanisms illustrate a multilayered control of RTK signaling exerted by the trafficking machinery. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved. Source

Rosta E.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Nowotny M.,International Institute of Molecular and Cell Biology | Yang W.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Hummer G.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases
Journal of the American Chemical Society

We use quantum mechanics/molecular mechanics simulations to study the cleavage of the ribonucleic acid (RNA) backbone catalyzed by ribonuclease H. This protein is a prototypical member of a large family of enzymes that use two-metal catalysis to process nucleic acids. By combining Hamiltonian replica exchange with a finite-temperature string method, we calculate the free energy surface underlying the RNA-cleavage reaction and characterize its mechanism. We find that the reaction proceeds in two steps. In a first step, catalyzed primarily by magnesium ion A and its ligands, a water molecule attacks the scissile phosphate. Consistent with thiol-substitution experiments, a water proton is transferred to the downstream phosphate group. The transient phosphorane formed as a result of this nucleophilic attack decays by breaking the bond between the phosphate and the ribose oxygen. In the resulting intermediate, the dissociated but unprotonated leaving group forms an alkoxide coordinated to magnesium ion B. In a second step, the reaction is completed by protonation of the leaving group, with a neutral Asp132 as a likely proton donor. The overall reaction barrier of ∼15 kcal mol-1, encountered in the first step, together with the cost of protonating Asp132, is consistent with the slow measured rate of ∼1-100/min. The two-step mechanism is also consistent with the bell-shaped pH dependence of the reaction rate. The nonmonotonic relative motion of the magnesium ions along the reaction pathway agrees with X-ray crystal structures. Proton-transfer reactions and changes in the metal ion coordination emerge as central factors in the RNA-cleavage reaction. © 2011 American Chemical Society. Source

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