Neurofilaments Function as Shock Absorbers: Compression Response Arising from Disordered Proteins

Kornreich, Micha; Malka-Gibor, Eti; Zuker, Ben; Laser-Azogui, Adi; Beck, Roy

doi:10.1103/physrevlett.117.148101

Cited by 31 publications

(60 citation statements)

References 49 publications

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“…The unexpectedly collapsed conformation of phosphorylated NF-LM may involve interactions between NF-M segments with either NF-L or NF-M segments, as recently shown (29,34). Here, upon de-phosphorylation, new NF-M attractive binding sites are formed further away from the filament backbone (Fig.…”

Section: Resultsmentioning

confidence: 67%

Phosphorylation-Induced Mechanical Regulation of Intrinsically Disordered Neurofilament Proteins

Malka-Gibor

Kornreich

Laser-Azogui

et al. 2017

Biophysical Journal

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The biological function of protein assemblies has been conventionally equated with a unique three-dimensional protein structure and protein-specific interactions. However, in the past 20 years it has been found that some assemblies contain long flexible regions that adopt multiple structural conformations. These include neurofilament proteins that constitute the stress-responsive supportive network of neurons. Herein, we show that the macroscopic properties of neurofilament networks are tuned by enzymatic regulation of the charge found on the flexible protein regions. The results reveal an enzymatic (phosphorylation) regulation of macroscopic properties such as orientation, stress response, and expansion in flexible protein assemblies. Using a model that explains the attractive electrostatic interactions induced by enzymatically added charges, we demonstrate that phosphorylation regulation is far richer and versatile than previously considered.

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Section: Resultsmentioning

confidence: 67%

Phosphorylation-Induced Mechanical Regulation of Intrinsically Disordered Neurofilament Proteins

Malka-Gibor

Kornreich

Laser-Azogui

et al. 2017

Biophysical Journal

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“…A large number of natively supercharged proteins have a disordered structure. The supercharged unstructured proteins steer phase separations, provide mechanical properties, and assist in calcium storage of cells . Thereby, natural supercharged proteins harbor essential functions for biology.…”

Section: Introductionmentioning

confidence: 99%

Supercharged Proteins and Polypeptides

Malessa

Boersma

et al. 2020

Advanced Materials

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Electrostatic interactions play a vital role in nature. Biomacromolecules such as proteins are orchestrated by electrostatics, among other intermolecular forces, to assemble and organize biochemistry. Natural proteins with a high net charge exist in a folded state or are unstructured and can be an inspiration for scientists to artificially supercharge other protein entities. Recent findings show that supercharging proteins allows for control of their properties such as temperature resistance and catalytic activity. One elegant method to transfer the favorable properties of supercharged proteins to other proteins is the fabrication of fusions. Genetically engineered, supercharged unstructured polypeptides (SUPs) are just one promising fusion tool. SUPs can also be complexed with artificial entities to yield thermotropic and lyotropic liquid crystals and liquids. These architectures represent novel bulk materials that are sensitive to external stimuli. Interestingly, SUPs undergo fluid–fluid phase separation to form coacervates. These coacervates can even be directly generated in living cells or can be combined with dissipative fiber assemblies that induce life‐like features. Supercharged proteins and SUPs are developed into exciting classes of materials. Their synthesis, structures, and properties are summarized. Moreover, potential applications are highlighted and challenges are discussed.

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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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Neurofilaments Function as Shock Absorbers: Compression Response Arising from Disordered Proteins

Cited by 31 publications

References 49 publications

Phosphorylation-Induced Mechanical Regulation of Intrinsically Disordered Neurofilament Proteins

Phosphorylation-Induced Mechanical Regulation of Intrinsically Disordered Neurofilament Proteins

Supercharged Proteins and Polypeptides

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

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