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Inositol hexakisphosphate increases the size of platelet aggregates

Abstract (Expand)

The inositol phosphates, InsP5 and InsP6, have recently been identified as binding partners of fibrinogen, which is critically involved in hemostasis by crosslinking activated platelets at sites of … vascular injury. Here, we investigated the putative physiological role of this interaction and found that platelets increase their InsP6 concentration upon stimulation with the PLC-activating agonists thrombin, collagen I and ADP and present a fraction of it at the outer plasma membrane. Cone and plate analysis in whole blood revealed that InsP6 specifically increases platelet aggregate size. This effect is fibrinogen-dependent, since it is inhibited by an antibody that blocks fibrinogen binding to platelets. Furthermore, InsP6 has only an effect on aggregate size of washed platelets when fibrinogen is present, while it has no influence in presence of von Willebrand factor or collagen. By employing blind docking studies we predicted the binding site for InsP6 at the bundle between the γand βhelical subunit of fibrinogen. Since InsP6 is unable to directly activate platelets and it did not exhibit an effect on thrombin formation or fibrin structure, our data indicate that InsP6 might be a hemostatic agent that is produced by platelets upon stimulation with PLC-activating agonists to promote platelet aggregation by supporting crosslinking of fibrinogen and activated platelets.

Authors: Maria A. Brehm, Ulrike Klemm, Christoph Rehbach, Nina Erdmann, Katra Kolšek, Hongying Lin, Camilo Aponte-Santamaría, Frauke Gräter, Bernhard H. Rauch, Andrew M. Riley, Georg W. Mayr, Barry V.L. Potter, Sabine Windhorst

Date Published: 1st Mar 2019

Publication Type: Journal

How ARVC-Related Mutations Destabilize Desmoplakin: An MD Study

Abstract (Expand)

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial heart disease linked to mutations in several desmosomal proteins, but the specific effects of these mutations on the molecular level … are poorly understood. Among the many documented ARVC-related genetic variants, a striking hotspot of nine mutations has been identified in the plakin domain of desmoplakin. This hotspot can be found at the meeting point of three different subdomains of desmoplakin: two spectrin repeats and a Src homology 3 domain. We set out to understand the effect of these mutations. We determine, using molecular dynamics simulations, how these mutations affect the mechanics of this interface, performing two different classes of simulations. First, we sample the dynamics of the plakin domain, in particular the tendency of the interdomain hinge to buckle, and then we apply an external force onto the constructs and determine the force necessary to break them. We find that surface-exposed mutations are not affecting the dynamics to a very large degree but that most buried mutations make the junction more flexible and decrease the rupture forces observed. Our data suggest that buried ARVC mutations destabilize desmoplakin and thereby impair desmosome integrity under tension.

Authors: Csaba Daday, Laura Marlene Mateyka, Frauke Gräter

Date Published: 1st Mar 2019

Publication Type: Journal

Topology-Driven Single-Molecule Conductance of Carbon Nanothreads

Abstract (Expand)

Highly conductive single-molecule junctions typically involve π-conjugated molecular bridges, whose frontier molecular orbital energy levels can be fine-tuned to best match the Fermi level of the leads. … Fully saturated wires, e.g., alkanes, are typically thought of as insulating rather than highly conductive. However, in this work, we demonstrate in silico that significant zero-bias conductance can be achieved in such systems by means of topology. Specifically, caged saturated hydrocarbons offering multiple σ-conductance channels afford transmission far beyond what could be expected based upon conventional superposition laws, particularly if these pathways are composed entirely from quaternary carbon atoms. Computed conductance of molecular bridges based on carbon nanothreads, e.g., polytwistane, is not only of appreciable magnitude; it also shows a very slow decay with increasing nanogap, similarly to the case of π-conjugated wires. These findings offer a way to manipulate the transport properties of molecular systems by means of their topology, alternatively to the traditionally invoked electronic structure.

Authors: Ganna Gryn’ova, Clémence Corminboeuf

Date Published: 11th Feb 2019

Publication Type: Journal

Influence of Transmembrane Helix Mutations on Cytochrome P450-Membrane Interactions and Function

Abstract

Not specified

Authors: Ghulam Mustafa, Prajwal P. Nandekar, Tyler J. Camp, Neil J. Bruce, Michael C. Gregory, Stephen G. Sligar, Rebecca C. Wade

Date Published: 1st Feb 2019

Publication Type: Journal

Identifying a First-Order Phase Transition in Neutron-Star Mergers through Gravitational Waves

Abstract

Not specified

Authors: Andreas Bauswein, Niels-Uwe F. Bastian, David B. Blaschke, Katerina Chatziioannou, James A. Clark, Tobias Fischer, Micaela Oertel

Date Published: 1st Feb 2019

Publication Type: Journal

Observing the post-merger signal of GW170817-like events with improved gravitational-wave detectors

Abstract

Not specified

Authors: Andoni Torres-Rivas, Katerina Chatziioannou, Andreas Bauswein, James Alexander Clark

Date Published: 1st Feb 2019

Publication Type: Journal

Remnants and ejecta of thermonuclear electron-capture supernovae. Constraining oxygen-neon deflagrations in high-density white dwarfs

Abstract

Not specified

Authors: S. Jones, F. K. Röpke, C. Fryer, A. J. Ruiter, I. R. Seitenzahl, L. R. Nittler, S. T. Ohlmann, R. Reifarth, M. Pignatari, K. Belczynski

Date Published: 1st Feb 2019

Publication Type: Journal

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