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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

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

Structure and dynamics of the platelet integrin-binding C4 domain of von Willebrand factor

Abstract (Expand)

Von Willebrand factor (VWF) is a key player in the regulation of hemostasis by promoting recruitment of platelets to sites of vascular injury. An array of 6 C domains forms the dimeric C-terminal VWF … stem. Upon shear force activation, the stem adopts an open conformation allowing the adhesion of VWF to platelets and the vessel wall. To understand the underlying molecular mechanism and associated functional perturbations in disease-related variants, knowledge of high-resolution structures and dynamics of C domains is of paramount interest. Here, we present the solution structure of the VWF C4 domain, which binds to the platelet integrin and is therefore crucial for the VWF function. In the structure, we observed 5 intra- and inter-subdomain disulfide bridges, of which 1 is unique in the C4 domain. The structure further revealed an unusually hinged 2-subdomain arrangement. The hinge is confined to a very short segment around V2547 connecting the 2 subdomains. Together with 2 nearby inter-subdomain disulfide bridges, this hinge induces slow conformational changes and positional alternations of both subdomains with respect to each other. Furthermore, the structure demonstrates that a clinical gain-of-function VWF variant (Y2561) is more likely to have an effect on the arrangement of the C4 domain with neighboring domains rather than impairing platelet integrin binding.

Authors: Emma-Ruoqi Xu, Sören von Bülow, Po-Chia Chen, Peter J. Lenting, Katra Kolšek, Camilo Aponte-Santamaría, Bernd Simon, Jaelle Foot, Tobias Obser, Reinhard Schneppenheim, Frauke Gräter, Cécile V. Denis, Matthias Wilmanns, Janosch Hennig

Date Published: 24th Jan 2019

Publication Type: Journal

Multi-model combination and seamless prediction

Abstract

Not specified

Author: Stephan Hemri

Date Published: 2019

Publication Type: InCollection

Extraction of Spatial-Temporal Features of Bus Loads in Electric Grids through Clustering in a Dynamic Model Space

Abstract

Not specified

Authors: Wei Zhang, Gang Mu, Chen Song, Gangui Yan, Vincent Heuveline

Date Published: 2019

Publication Type: Journal

Data Management in Computational Systems Biology: Exploring Standards, Tools, Databases, and Packaging Best Practices

Abstract

Not specified

Authors: Natalie J. Stanford, Martin Scharm, Paul D. Dobson, Martin Golebiewski, Michael Hucka, Varun B. Kothamachu, David Nickerson, Stuart Owen, Jürgen Pahle, Ulrike Wittig, Dagmar Waltemath, Carole Goble, Pedro Mendes, Jacky Snoep

Date Published: 2019

Publication Type: InBook

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