Ensemble Calculation for Intrinsically Disordered Proteins Using NMR Parameters

Kragelj, Jaka; Blackledge, Martin; Jensen, Malene Ringkjøbing

doi:10.1007/978-3-319-20164-1_4

Cited by 20 publications

(17 citation statements)

References 95 publications

(103 reference statements)

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“…A problem in the past was that computational models of IDPs were overly compact [ 114 ] but this issue is being addressed through the method refinement [ 112 , 115 – 117 ] and consideration of NMR, SAXS and smFRET data [ 110 , 113 , 118 ]. Another group of approaches utilize experimental restraints (e.g., NMR and/or SAXS data) to select conformers for inclusion within IDP ensembles—the so-called “sample-and-select” methods [ 88 , 119 – 121 ]. Complementary computational methods have been developed for generating IDP ensembles based on SAXS data [ 122 ].…”

Section: Introductionmentioning

confidence: 99%

Phase separation in biology; functional organization of a higher order

2016

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Inside eukaryotic cells, macromolecules are partitioned into membrane-bounded compartments and, within these, some are further organized into non-membrane-bounded structures termed membrane-less organelles. The latter structures are comprised of heterogeneous mixtures of proteins and nucleic acids and assemble through a phase separation phenomenon similar to polymer condensation. Membrane-less organelles are dynamic structures maintained through multivalent interactions that mediate diverse biological processes, many involved in RNA metabolism. They rapidly exchange components with the cellular milieu and their properties are readily altered in response to environmental cues, often implicating membrane-less organelles in responses to stress signaling. In this review, we discuss: (1) the functional roles of membrane-less organelles, (2) unifying structural and mechanistic principles that underlie their assembly and disassembly, and (3) established and emerging methods used in structural investigations of membrane-less organelles.

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Section: Introductionmentioning

confidence: 99%

Phase separation in biology; functional organization of a higher order

2016

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“…Characterization of the structural ensemble is key for capturing the specific flexibility of the structure, and provides a means to define bounds for the spread of conformations accessible to a dynamic molecule. Various methods of ensemble analysis exist for different available structural data sets, in particular in application to intrinsically disordered proteins (IDPs) …”

Section: Introductionmentioning

confidence: 99%

Tropoelastin is a Flexible Molecule that Retains its Canonical Shape

Tarakanova

Yeo

Baldock

et al. 2018

Macromolecular Bioscience

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in elastic tissues including blood vessels, skin, and lungs. [1,2] The mature form of the secreted human tropoelastin monomer is 60 kDa [3] and is composed of an alternating pattern of repetitive, hydrophobic glycine-, valine-, and proline-rich domains spread out between lysine-containing cross-linking domains. [4] Traditionally described as a largely disordered molecule, recent studies suggest that tropoelastin is a flexible molecule with a distinct nanostructure [5][6][7] that determines its structural and cell-adhesive properties.Tropoelastin's distinct nanostructure determines its propensity to assemble into higher-order structures (Figure 1) through elastogenesis. [8] Elastogenesis begins with self-assembly of the ≈15 nm monomers, a process called coacervation. [9] Self-assembly, naturally occurring at physiological pH and salt conditions at 37 °C, results in spherical structures from 200 nm to 6 µm in diameter. [9][10][11] Spherule formation through coacervation begins at the cell surface by surface-tethered tropoelastin molecules, until released for integration into the growing elastic fiber. Tropoelastin aggregates adhere to the cell surface through GAG-and integrin-mediated interactions at specific interaction sites. [12][13][14][15][16][17][18] Spherules are deposited on a microfibrillar scaffold where they are stabilized Tropoelastin Tropoelastin is the dominant building block of elastic fibers, which form a major component of the extracellular matrix, providing structural support to tissues and imbuing them with elasticity and resilience. Recently, the atomistic structure of human tropoelastin is described, obtained through accelerated sampling via replica exchange molecular dynamics simulations. Here, principal component analysis is used to consider the ensemble of structures accessible to tropoelastin at body temperature (37 °C) at which tropoelastin naturally self-assembles into aggregated coacervates. These coacervates are relevant because they are an essential intermediate assembly stage, where tropoelastin molecules are then cross-linked at lysine residues and integrated into growing elastic fibers. It is found that the ensemble preserves the canonical tropoelastin structure with an extended molecular body flanked by two protruding legs, and identifies variations in specific domain positioning within this global shape. Furthermore, it is found that lysine residues show a large variation in their location on the tropoelastin molecule compared with other residues. It is hypothesized that this perturbation of the lysines increases their accessibility and enhances cross-linking. Finally, the principal component modes are extracted to describe the range of tropoelastin's conformational fluctuation to validate tropoelastin's scissor-twist motion that was predicted earlier.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.

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“…These values are normally less than 10% and are expected to remarkably increase in frequency in the presence of a detectable effect the ∆G D -D upon mutation. Ever since the discovery of IDPs, it has been observed that these proteins in isolation may retain a considerable amount of embryonic structure [50][51][52][53], which may considerably vary from case to case and can be experimentally addressed with different experimental techniques such as NMR or SAXS [54][55][56]. Therefore, since mutagenesis may potentially perturb these structures, when evaluating IDPs as candidates for the Φ values analysis, it is important to take into account these possible effects.…”

Section: The Residual Structure Of Idpsmentioning

confidence: 99%

Understanding the Binding Induced Folding of Intrinsically Disordered Proteins by Protein Engineering: Caveats and Pitfalls

Malagrinò

Visconti

Pagano

et al. 2020

IJMS

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Many proteins lack a well-defined three-dimensional structure in isolation. These proteins, typically denoted as intrinsically disordered proteins (IDPs), may display a characteristic disorder-to-order transition when binding their physiological partner(s). From an experimental perspective, it is of great importance to establish the general grounds to understand how such folding processes may be explored. Here we discuss the caveats and the pitfalls arising when applying to IDPs one of the key techniques to characterize the folding of globular proteins, the Φ value analysis. This method is based on measurements of the free energy changes of transition and native states upon conservative, non-disrupting, mutations. On the basis of available data, we reinforce the validity of Φ value analysis in the study of IDPs and suggest future experiments to further validate this powerful experimental method.

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Ensemble Calculation for Intrinsically Disordered Proteins Using NMR Parameters

Cited by 20 publications

References 95 publications

Phase separation in biology; functional organization of a higher order

Phase separation in biology; functional organization of a higher order

Tropoelastin is a Flexible Molecule that Retains its Canonical Shape

Understanding the Binding Induced Folding of Intrinsically Disordered Proteins by Protein Engineering: Caveats and Pitfalls

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