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75 Publications visible to you, out of a total of 75
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

Advances in molecular simulations of protein mechanical properties and function

Abstract (Expand)

Single-molecule force spectroscopy and classical molecular dynamics are natural allies. Recent advances in both experiments and simulations have increasingly facilitated a direct comparison of SMFS and … MD data, most importantly by closing the gap between time scales, which has been traditionally at least 5 orders of magnitudes wide. In this review, we will explore these advances chiefly on the computational side. We focus on protein dynamics under force and highlight recent studies that showcase how lower loading rates and more statistics help to better interpret previous experiments and to also motivate new ones. At the same time, steadily increasing system sizes are used to mimic more closely the mechanical environment in the biological context. We showcase some of these advances on atomistic and coarse-grained scale, from asymmetric membrane tension to larger (multidomain/multimeric) protein assemblies under force.

Authors: Florian Franz, Csaba Daday, Frauke Gräter

Date Published: 1st Apr 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

The plakin domain of C. elegans VAB-10/plectin acts as a hub in a mechanotransduction pathway to promote morphogenesis

Abstract

Not specified

Authors: Shashi Kumar Suman, Csaba Daday, Teresa Ferraro, Thanh Vuong-Brender, Saurabh Tak, Sophie Quintin, François Robin, Frauke Gräter, Michel Labouesse

Date Published: 13th Dec 2019

Publication Type: Journal

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