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23 Publications visible to you, out of a total of 23
Phosphorylation tunes elongation propensity and cohesiveness of INCENP's intrinsically disordered region.

Abstract (Expand)

The inner centromere protein, INCENP, is crucial for correct chromosome segregation during mitosis. It connects the kinase Aurora B to the inner centromere allowing this kinase to dynamically access … its kinetochore targets. However, the function of its central, 440-residue long intrinsically disordered region (IDR) and its multiple phosphorylation sites is unclear. Here, we determined the conformational ensemble of INCENP's IDR, systematically varying the level of phosphorylation, using all-atom and coarse-grain molecular dynamics simulations. Our simulations show that phosphorylation expands INCENP's IDR, both locally and globally, mainly by increasing its overall net charge. The disordered region undergoes critical globule-to-coil conformational transitions and the transition temperature non-monotonically depends on the degree of phosphorylation, with a mildly phosphorylated case of neutral net charge featuring the highest collapse propensity. The IDR transitions from a multitude of globular states, accompanied by several specific internal contacts that reduce INCENP length by loop formation, to weakly interacting and highly extended coiled conformations. Phosphorylation critically shifts the population between these two regimes. It thereby influences cohesiveness and phase behavior of INCENP IDR assemblies, a feature presumably relevant for INCENP's function in the chromosomal passenger complex. Overall, we propose the disordered region of INCENP to act as a phosphorylation-regulated and length-variable component, within the previously defined "dog-leash" model, that thereby regulates how Aurora B reaches its targets for proper chromosome segregation.

Authors: Isabel M Martin, Camilo Aponte-Santamaría, Lisa Schmidt, Marius Hedtfeld, Adel Iusupov, Andrea Musacchio, Frauke Gräter

Date Published: 15th Jan 2022

Publication Type: Journal

Longitudinal strand ordering leads to shear thinning in Nafion.

Abstract

hts into the mechanism governing the shear thinning effects observed in Nafion solutions, through the use of non-equilibrium, coarse-grained, molecular dynamic simulations.

Authors: Nicholas Michelarakis, Florian Franz, Konstantinos Gkagkas, Frauke Gräter

Date Published: 24th Nov 2021

Publication Type: Journal

Kinetic and structural roles for the surface in guiding SAS-6 self-assembly to direct centriole architecture

Abstract (Expand)

iscovering mechanisms governing organelle assembly is a fundamental pursuit in biology. The centriole is an evolutionarily conserved organelle with a signature 9-fold symmetrical chiral arrangement of … microtubules imparted onto the cilium it templates. The first structure in nascent centrioles is a cartwheel, which comprises stacked 9-fold symmetrical SAS-6 ring polymers emerging orthogonal to a surface surrounding each resident centriole. The mechanisms through which SAS-6 polymerization ensures centriole organelle architecture remain elusive. We deploy photothermally-actuated off-resonance tapping high-speed atomic force microscopy to decipher surface SAS-6 self-assembly mechanisms. We show that the surface shifts the reaction equilibrium by ~104 compared to solution. Moreover, coarse-grained molecular dynamics and atomic force microscopy reveal that the surface converts the inherent helical propensity of SAS-6 polymers into 9-fold rings with residual asymmetry, which may guide ring stacking and impart chiral features to centrioles and cilia. Overall, our work reveals fundamental design principles governing centriole assembly.

Authors: Niccolò Banterle, Adrian P. Nievergelt, Svenja de Buhr, Georgios N. Hatzopoulos, Charlène Brillard, Santiago Andany, Tania Hübscher, Frieda A. Sorgenfrei, Ulrich S. Schwarz, Frauke Gräter, Georg E. Fantner, Pierre Gönczy

Date Published: 26th Oct 2021

Publication Type: Journal

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

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