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91 Publications visible to you, out of a total of 91
ColBuilder: A server to build collagen fibril models.

Abstract (Expand)

Type I collagen is the main structural component of many tissues in the human body. It provides excellent mechanical properties to connective tissue and acts as a protein interaction hub. There is thus … a wide interest in understanding the properties and diverse functions of type I collagen at the molecular level. A precondition is an atomistic collagen I structure as it occurs in native tissue. To this end, we built full-atom models of cross-linked collagen fibrils by integrating the low-resolution structure of collagen fibril available from x-ray fiber diffraction with high-resolution structures of short collagen-like peptides from x-ray crystallography and mass spectrometry data. We created a Web resource of collagen models for 20 different species with a large variety of cross-link types and localization within the fibril to facilitate structure-based analyses and simulations of type I collagen in health and disease. To easily enable simulations, we provide parameters of the modeled cross-links for an Amber force field. The repository of collagen models is available at https://colbuilder.h-its.org.

Authors: Agnieszka Obarska-Kosinska, Benedikt Rennekamp, Aysecan Ünal, Frauke Gräter

Date Published: 7th Sep 2021

Publication Type: Journal

How multisite phosphorylation impacts the conformations of intrinsically disordered proteins.

Abstract (Expand)

Phosphorylation of intrinsically disordered proteins (IDPs) can produce changes in structural and dynamical properties and thereby mediate critical biological functions. How phosphorylation effects … intrinsically disordered proteins has been studied for an increasing number of IDPs, but a systematic understanding is still lacking. Here, we compare the collapse propensity of four disordered proteins, Ash1, the C-terminal domain of RNA polymerase (CTD2'), the cytosolic domain of E-Cadherin, and a fragment of the p130Cas, in unphosphorylated and phosphorylated forms using extensive all-atom molecular dynamics (MD) simulations. We find all proteins to show V-shape changes in their collapse propensity upon multi-site phosphorylation according to their initial net charge: phosphorylation expands neutral or overall negatively charged IDPs and shrinks positively charged IDPs. However, force fields including those tailored towards and commonly used for IDPs overestimate these changes. We find quantitative agreement of MD results with SAXS and NMR data for Ash1 and CTD2' only when attenuating protein electrostatic interactions by using a higher salt concentration (e.g. 350 mM), highlighting the overstabilization of salt bridges in current force fields. We show that phosphorylation of IDPs also has a strong impact on the solvation of the protein, a factor that in addition to the actual collapse or expansion of the IDP should be considered when analyzing SAXS data. Compared to the overall mild change in global IDP dimension, the exposure of active sites can change significantly upon phosphorylation, underlining the large susceptibility of IDP ensembles to regulation through post-translational modifications.

Authors: Fan Jin, Frauke Gräter

Date Published: 4th May 2021

Publication Type: Journal

Coarse-Grained Simulation of Mechanical Properties of Single Microtubules With Micrometer Length.

Abstract (Expand)

Microtubules are one of the most important components in the cytoskeleton and play a vital role in maintaining the shape and function of cells. Because single microtubules are some micrometers long, … it is difficult to simulate such a large system using an all-atom model. In this work, we use the newly developed convolutional and K-means coarse-graining (CK-CG) method to establish an ultra-coarse-grained (UCG) model of a single microtubule, on the basis of the low electron microscopy density data of microtubules. We discuss the rationale of the micro-coarse-grained microtubule models of different resolutions and explore microtubule models up to 12-micron length. We use the devised microtubule model to quantify mechanical properties of microtubules of different lengths. Our model allows mesoscopic simulations of micrometer-level biomaterials and can be further used to study important biological processes related to microtubule function.

Authors: Jinyin Zha, Yuwei Zhang, Kelin Xia, Frauke Gräter, Fei Xia

Date Published: 15th Feb 2021

Publication Type: Journal

Electrostatic interactions contribute to the control of intramolecular thiol–disulfide isomerization in a protein

Abstract (Expand)

of structural factors and of electrostatic interactions with the environment on the outcome of thiol–disulfide exchange reactions were investigated in a mutated immunoglobulin domain (I27*) under …r mechanical stress.

Authors: Denis Maag, Marina Putzu, Claudia L. Gómez-Flores, Frauke Gräter, Marcus Elstner, Tomáš Kubař

Date Published: 2021

Publication Type: Journal

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

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