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23 Publications visible to you, out of a total of 23
Gain-of-Function Variant p.Pro2555Arg of von Willebrand Factor Increases Aggregate Size through Altering Stem Dynamics.

Abstract (Expand)

The multimeric plasma glycoprotein (GP) von Willebrand factor (VWF) is best known for recruiting platelets to sites of injury during primary hemostasis. Generally, mutations in the VWF gene lead to … loss of hemostatic activity and thus the bleeding disorder von Willebrand disease. By employing cone and platelet aggregometry and microfluidic assays, we uncovered a platelet GPIIb/IIIa-dependent prothrombotic gain of function (GOF) for variant p.Pro2555Arg, located in the C4 domain, leading to an increase in platelet aggregate size. We performed complementary biophysical and structural investigations using circular dichroism spectra, small-angle X-ray scattering, nuclear magnetic resonance spectroscopy, molecular dynamics simulations on the single C4 domain, and dimeric wild-type and p.Pro2555Arg constructs. C4-p.Pro2555Arg retained the overall structural conformation with minor populations of alternative conformations exhibiting increased hinge flexibility and slow conformational exchange. The dimeric protein becomes disordered and more flexible. Our data suggest that the GOF does not affect the binding affinity of the C4 domain for GPIIb/IIIa. Instead, the increased VWF dimer flexibility enhances temporal accessibility of platelet-binding sites. Using an interdisciplinary approach, we revealed that p.Pro2555Arg is the first VWF variant, which increases platelet aggregate size and shows a shear-dependent function of the VWF stem region, which can become hyperactive through mutations. Prothrombotic GOF variants of VWF are a novel concept of a VWF-associated pathomechanism of thromboembolic events, which is of general interest to vascular health but not yet considered in diagnostics. Thus, awareness should be raised for the risk they pose. Furthermore, our data implicate the C4 domain as a novel antithrombotic drug target. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Authors: Volker Huck, Po-Chia Chen, Emma-Ruoqi Xu, Alexander Tischer, Ulrike Klemm, Camilo Aponte-Santamaría, Christian Mess, Tobias Obser, Fabian Kutzki, Gesa König, Cécile V. Denis, Frauke Gräter, Matthias Wilmanns, Matthew Auton, Stefan W Schneider, Reinhard Schneppenheim, Janosch Hennig, Maria A. Brehm

Date Published: 31st Dec 2020

Publication Type: Journal

Mechanical characterization and induced crystallization in nanocomposites of thermoplastics and carbon nanotubes

Abstract (Expand)

Nanocomposites built from polymers and carbon nanotubes (CNTs) are a promising class of materials. Computer modeling can provide nanoscale views of the polymer-CNT interface, which are much needed to … foster the manufacturing and development of such materials. However, setting up periodic nanocomposite models is a challenging task. Here we propose a computational workflow based on Molecular Dynamics simulations. We demonstrate its capabilities and showcase its applications, focusing on two existing nanocomposite materials: polystyrene (PS) with CNT and polyether ether ketone with CNT. The models provide insights into the polymer crystallization inside CNTs. Furthermore, the PS+CNT nanocomposite models are mechanically tested and able to predict an enhancement in Young's modulus due to the addition of highly dispersed CNTs. We accompany those results with experimental tests and provide a prediction model based on Dynamic Quantized Fracture Mechanics theory. Our study proposes representative simulations of polymer-CNT nanocomposites as promising tools to guide the rational design of this class of materials.

Authors: Eduardo R. Cruz-Chú, Gonzalo Villegas-Rodriguez, Tobias Jäger, Luca Valentini, Nicola Pugno, Konstantinos Gkagkas, Frauke Gräter

Date Published: 12th Oct 2020

Publication Type: Journal

Structural basis of Focal Adhesion Kinase activation on lipid membranes.

Abstract (Expand)

Focal adhesion kinase (FAK) is a key component of the membrane proximal signaling layer in focal adhesion complexes, regulating important cellular processes, including cell migration, proliferation, … and survival. In the cytosol, FAK adopts an autoinhibited state but is activated upon recruitment into focal adhesions, yet how this occurs or what induces structural changes is unknown. Here, we employ cryo-electron microscopy to reveal how FAK associates with lipid membranes and how membrane interactions unlock FAK autoinhibition to promote activation. Intriguingly, initial binding of FAK to the membrane causes steric clashes that release the kinase domain from autoinhibition, allowing it to undergo a large conformational change and interact itself with the membrane in an orientation that places the active site toward the membrane. In this conformation, the autophosphorylation site is exposed and multiple interfaces align to promote FAK oligomerization on the membrane. We show that interfaces responsible for initial dimerization and membrane attachment are essential for FAK autophosphorylation and resulting cellular activity including cancer cell invasion, while stable FAK oligomerization appears to be needed for optimal cancer cell proliferation in an anchorage-independent manner. Together, our data provide structural details of a key membrane bound state of FAK that is primed for efficient autophosphorylation and activation, hence revealing the critical event in integrin mediated FAK activation and signaling at focal adhesions.

Authors: Iván Acebrón, Ricardo D Righetto, Christina Schoenherr, Svenja de Buhr, Pilar Redondo, Jayne Culley, Carlos F Rodríguez, Csaba Daday, Nikhil Biyani, Oscar Llorca, Adam Byron, Mohamed Chami, Frauke Gräter, Jasminka Boskovic, Margaret C Frame, Henning Stahlberg, Daniel Lietha

Date Published: 1st Oct 2020

Publication Type: Journal

Mechanoradicals in tensed tendon collagen as a source of oxidative stress

Abstract (Expand)

As established nearly a century ago, mechanoradicals originate from homolytic bond scission in polymers. The existence, nature and biological relevance of mechanoradicals in proteins, instead, are … unknown. We here show that mechanical stress on collagen produces radicals and subsequently reactive oxygen species, essential biological signaling molecules. Electron-paramagnetic resonance (EPR) spectroscopy of stretched rat tail tendon, atomistic molecular dynamics simulations and quantum-chemical calculations show that the radicals form by bond scission in the direct vicinity of crosslinks in collagen. Radicals migrate to adjacent clusters of aromatic residues and stabilize on oxidized tyrosyl radicals, giving rise to a distinct EPR spectrum consistent with a stable dihydroxyphenylalanine (DOPA) radical. The protein mechanoradicals, as a yet undiscovered source of oxidative stress, finally convert into hydrogen peroxide. Our study suggests collagen I to have evolved as a radical sponge against mechano-oxidative damage and proposes a mechanism for exercise-induced oxidative stress and redox-mediated pathophysiological processes.

Authors: Christopher Zapp, Agnieszka Obarska-Kosinska, Benedikt Rennekamp, Markus Kurth, David M Hudson, Davide Mercadante, Uladzimir Barayeu, Tobias P Dick, Vasyl Denysenkov, Thomas Prisner, Marina Bennati, Csaba Daday, Reinhard Kappl, Frauke Gräter

Date Published: 8th May 2020

Publication Type: Journal

Hybrid Kinetic Monte Carlo/Molecular Dynamics Simulations of Bond Scissions in Proteins

Abstract

Not specified

Authors: Benedikt Rennekamp, Fabian Kutzki, Agnieszka Obarska-Kosinska, Christopher Zapp, Frauke Gräter

Date Published: 16th Jan 2020

Publication Type: Journal

Emergence of Hierarchical Modularity in Evolving Networks Uncovered by Phylogenomic Analysis.

Abstract (Expand)

Networks describe how parts associate with each other to form integrated systems which often have modular and hierarchical structure. In biology, network growth involves two processes, one that unifies … and the other that diversifies. Here, we propose a biphasic (bow-tie) theory of module emergence. In the first phase, parts are at first weakly linked and associate variously. As they diversify, they compete with each other and are often selected for performance. The emerging interactions constrain their structure and associations. This causes parts to self-organize into modules with tight linkage. In the second phase, variants of the modules diversify and become new parts for a new generative cycle of higher level organization. The paradigm predicts the rise of hierarchical modularity in evolving networks at different timescales and complexity levels. Remarkably, phylogenomic analyses uncover this emergence in the rewiring of metabolomic and transcriptome-informed metabolic networks, the nanosecond dynamics of proteins, and evolving networks of metabolism, elementary functionomes, and protein domain organization.

Authors: Gustavo Caetano-Anollés, M Fayez Aziz, Fizza Mughal, Frauke Gräter, Ibrahim Koç, Kelsey Caetano-Anollés, Derek Caetano-Anollés

Date Published: 5th Sep 2019

Publication Type: Journal

Protein S-Bacillithiolation Functions in Thiol Protection and Redox Regulation of the Glyceraldehyde-3-Phosphate Dehydrogenase Gap in Staphylococcus aureus Under Hypochlorite Stress.

Abstract (Expand)

AIMS: Bacillithiol (BSH) is the major low-molecular-weight thiol of the human pathogen Staphylococcus aureus. In this study, we used OxICAT and Voronoi redox treemaps to quantify hypochlorite-sensitive … protein thiols in S. aureus USA300 and analyzed the role of BSH in protein S-bacillithiolation. RESULTS: The OxICAT analyses enabled the quantification of 228 Cys residues in the redox proteome of S. aureus USA300. Hypochlorite stress resulted in >10% increased oxidation of 58 Cys residues (25.4%) in the thiol redox proteome. Among the highly oxidized sodium hypochlorite (NaOCl)-sensitive proteins are five S-bacillithiolated proteins (Gap, AldA, GuaB, RpmJ, and PpaC). The glyceraldehyde-3-phosphate (G3P) dehydrogenase Gap represents the most abundant S-bacillithiolated protein contributing 4% to the total Cys proteome. The active site Cys151 of Gap was very sensitive to overoxidation and irreversible inactivation by hydrogen peroxide (H2O2) or NaOCl in vitro. Treatment with H2O2 or NaOCl in the presence of BSH resulted in reversible Gap inactivation due to S-bacillithiolation, which could be regenerated by the bacilliredoxin Brx (SAUSA300_1321) in vitro. Molecular docking was used to model the S-bacillithiolated Gap active site, suggesting that formation of the BSH mixed disulfide does not require major structural changes. Conclusion and Innovation: Using OxICAT analyses, we identified 58 novel NaOCl-sensitive proteins in the pathogen S. aureus that could play protective roles against the host immune defense and include the glycolytic Gap as major target for S-bacillithiolation. S-bacillithiolation of Gap did not require structural changes, but efficiently functions in redox regulation and protection of the active site against irreversible overoxidation in S. aureus. Antioxid. Redox Signal. 28, 410-430.

Authors: Marcel Imber, Nguyen Thi Thu Huyen, Agnieszka J. Pietrzyk-Brzezinska, Vu Van Loi, Melanie Hillion, Jörg Bernhardt, Lena Thärichen, Katra Kolšek, Malek Saleh, Chris J. Hamilton, Lorenz Adrian, Frauke Gräter, Markus C. Wahl, Haike Antelmann

Date Published: 20th Feb 2018

Publication Type: Journal

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