Paclitaxel suppresses Tau-mediated microtubule bundling in a concentration-dependent manner

Choi, Myung Chul; Chung, Peter J.; Song, Chaeyeon; Miller, Herbert C.; Kiris, Erkan; Li, Youli; Wilson, Leslie; Feinstein, Stuart C.; Safinya, Cyrus R.

doi:10.1016/j.bbagen.2016.09.011

Cited by 14 publications

(10 citation statements)

References 43 publications

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“…The challenge of structural biophysics is to determine the high-resolution structure of large self-assembled complexes, made of many subunits, in their biologically relevant solution conditions. Solution small-and wide-angle X-ray scattering (SAXS/WAXS) methods are one of the important label-free and highly sensitive bulk methods for investigating the structure of and interactions between complex molecular constructs (Rä dler et al, 1997;Koltover et al, 1998;Schilt et al, 2016;Dvir et al, 2013Dvir et al, , 2014Chung et al, 2015Chung et al, , 2016Lotan et al, 2016;Ojeda-Lopez et al, 2014;Moshe et al, 2013;Saper et al, 2012;Steiner et al, 2012;Szekely, Schilt et al, 2011;Nadler et al, 2011;Choi et al, 2009Choi et al, , 2016Wong et al, 2000;Deek et al, 2013;Beck et al, 2010;Kornreich et al, 2016;Shaharabani et al, 2016;Ginsburg et al, 2017;Asor et al, 2017;Fink et al, 2017). With modern synchrotron facilities the temporal and spatial resolution of these methods has been greatly improved (Ginsburg et al, 2016;Kler et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

D+: software for high-resolution hierarchical modeling of solution X-ray scattering from complex structures

et al. 2019

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This paper presents the computer program D+ (https://scholars.huji.ac.il/ uriraviv/book/d-0), where the reciprocal-grid (RG) algorithm is implemented. D+ efficiently computes, at high-resolution, the X-ray scattering curves from complex structures that are isotropically distributed in random orientations in solution. Structures are defined in hierarchical trees in which subunits can be represented by geometric or atomic models. Repeating subunits can be docked into their assembly symmetries, describing their locations and orientations in space. The scattering amplitude of the entire structure can be calculated by computing the amplitudes of the basic subunits on 3D reciprocal-space grids, moving up in the hierarchy, calculating the RGs of the larger structures, and repeating this process for all the leaves and nodes of the tree. For very large structures (containing over 100 protein subunits), a hybrid method can be used to avoid numerical artifacts. In the hybrid method, only grids of smaller subunits are summed and used as subunits in a direct computation of the scattering amplitude. D+ can accurately analyze both small-and wide-angle solution X-ray scattering data. This article describes how D+ applies the RG algorithm, accounts for rotations and translations of subunits, processes atomic models, accounts for the contribution of the solvent as well as the solvation layer of complex structures in a scalable manner, writes and accesses RGs, interpolates between grid points, computes numerical integrals, enables the use of scripts to define complicated structures, applies fitting algorithms, accounts for several coexisting uncorrelated populations, and accelerates computations using GPUs. D+ may also account for different X-ray energies to analyze anomalous solution X-ray scattering data. An accessory tool that can identify repeating subunits in a Protein Data Bank file of a complex structure is provided. The tool can compute the orientation and translation of repeating subunits needed for exploiting the advantages of the RG algorithm in D+. A Python wrapper (https://scholars. huji.ac.il/uriraviv/book/python-api) is also available, enabling more advanced computations and integration of D+ with other computational tools. Finally, a large number of tests are presented. The results of D+ are compared with those of other programs when possible, and the use of D+ to analyze solution scattering data from dynamic microtubule structures with different protofilament number is demonstrated. D+ and its source code are freely available for academic users and developers (https://bitbucket.org/uriraviv/public-dplus/src/ master/).

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Section: Introductionmentioning

confidence: 99%

D+: software for high-resolution hierarchical modeling of solution X-ray scattering from complex structures

et al. 2019

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“…The challenge of structural biophysics is to determine the high-resolution structure of large self-assembled complexes, made of many subunits, in their biologically relevant solution conditions. Solution small-and wide-angle X-ray scattering (SAXS/WAXS) methods are one of the important labelfree and highly sensitive bulk methods for investigating the structure and interactions between complex molecular constructs (Rädler et al, 1997;Koltover et al, 1998;Schilt et al, 2016;Dvir et al, 2014;Dvir et al, 2013;Chung et al, 2015;Chung et al, 2016;Lotan et al, 2016;Ojeda-Lopez et al, 2014;Moshe et al, 2013;Saper et al, 2012;Steiner et al, 2012;Szekely et al, 2011a;Szekely et al, 2011b;Choi et al, 2009;Choi et al, 2016;Wong et al, 2000;Deek et al, 2013;Beck et al, 2010;Kornreich et al, 2016;Shaharabani et al, 2016;Ginsburg et al, 2017;Asor et al, 2017;Fink et al, 2017a). With modern synchrotron facilities the temporal and spatial resolution of these methods has been greatly improved Kler et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

D+: Software for High-Resolution Hierarchical Modeling of Solution X-Ray Scattering from Complex Structures

Ginsburg¹,

Ben-Nun²,

Asor³

et al. 2018

Preprint

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<div>In this paper, we present our new computer program, D+, which uses the reciprocal-grid (RG) algorithm to efficiently compute X-ray scattering curves from solutions of complex structures at high-resolution. Structures are defined in hierarchical trees in which subunits can be represented by geometric or atomic models. Repeating subunits can be docked into their assembly symmetries, describing their locations and orientations in space. The scattering amplitude of the entire structure can be calculated by computing the amplitudes of the basic subunits on 3D reciprocal-space grids, moving up in the hierarchy, calculating the RGs of the larger structures, and by repeating this process for all the leaves and nodes of the tree. For very large structures, a Hybrid method can be used to avoid numerical artifacts. In the Hybrid method, only grids of smaller subunits are summed and used as subunits in a direct computation of the scattering amplitude. D+ can accurately analyze both small- and wide-angle solution X-ray scattering data. We present how D+ applies the RG algorithm, accounts for rotations and translations of subunits, processes atomic models, accounts for the contribution of the solvent as well as the solvation layer of complex structures in a scalable manner, writes and accesses RGs, interpolates between grid points, computes numerical integrals, enables the use of scripts to define complicated structures, applies fitting algorithms, accounts for several coexisting uncorrelated populations, and accelerates computations using GPUs. D+ may also account for different X-ray energies to analyze anomalous solution X-ray scattering data. An accessory tool that can identify repeating subunits in a protein data bank (PDB) file of a complex structure is provided. The tool can compute the orientation and translation of repeating subunits needed for exploiting the advantages of the RG algorithm in D+. In addition, a python wrapper is also available, enabling more advanced computations and integration of D+ with other computational tools. Finally, we present a large number of tests and compare the results of D+ with other programs when possible and demonstrate the use of D+ to analyze solution scattering data from dynamic microtubule structures with different protofilament number. D+ and its source code are freely available (https://scholars.huji.ac.il/uriraviv/software/d-software) for academic users and developers. </div>

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“…Bound tau protein is believed to form an electrostatic zipper with tau protein from neighboring microtubules (Fitzpatrick et al, 2017 ). As such, tau plays a critical role in stabilizing individual microtubules (Chung et al, 2015 ) and forming microtubule bundles (Choi et al, 2016 ). Increasing evidence suggests that axonal damage develops when a physical force is large enough to break the tau-microtubule bonds.…”

Section: Introductionmentioning

confidence: 99%

Physical Biology of Axonal Damage

Rooij

Kuhl

2018

Front. Cell. Neurosci.

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Excessive physical impacts to the head have direct implications on the structural integrity at the axonal level. Increasing evidence suggests that tau, an intrinsically disordered protein that stabilizes axonal microtubules, plays a critical role in the physical biology of axonal injury. However, the precise mechanisms of axonal damage remain incompletely understood. Here we propose a biophysical model of the axon to correlate the dynamic behavior of individual tau proteins under external physical forces to the evolution of axonal damage. To propagate damage across the scales, we adopt a consistent three-step strategy: First, we characterize the axonal response to external stretches and stretch rates for varying tau crosslink bond strengths using a discrete axonal damage model. Then, for each combination of stretch rates and bond strengths, we average the axonal force-stretch response of n = 10 discrete simulations, from which we derive and calibrate a homogenized constitutive model. Finally, we embed this homogenized model into a continuum axonal damage model of [1-d]-type in which d is a scalar damage parameter that is driven by the axonal stretch and stretch rate. We demonstrate that axonal damage emerges naturally from the interplay of physical forces and biological crosslinking. Our study reveals an emergent feature of the crosslink dynamics: With increasing loading rate, the axonal failure stretch increases, but axonal damage evolves earlier in time. For a wide range of physical stretch rates, from 0.1 to 10 /s, and biological bond strengths, from 1 to 100 pN, our model predicts a relatively narrow window of critical damage stretch thresholds, from 1.01 to 1.30, which agrees well with experimental observations. Our biophysical damage model can help explain the development and progression of axonal damage across the scales and will provide useful guidelines to identify critical damage level thresholds in response to excessive physical forces.

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Paclitaxel suppresses Tau-mediated microtubule bundling in a concentration-dependent manner

Abstract: Investigating MAP-mediated interactions between microtubules (as it relates to in vivo behavior) requires the elimination or minimization of paclitaxel.

Cited by 14 publications

References 43 publications

D+: software for high-resolution hierarchical modeling of solution X-ray scattering from complex structures

D+: software for high-resolution hierarchical modeling of solution X-ray scattering from complex structures

D+: Software for High-Resolution Hierarchical Modeling of Solution X-Ray Scattering from Complex Structures

Physical Biology of Axonal Damage

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