Analytical Description of NMR Relaxation Highlights Correlated Dynamics in Intrinsically Disordered Proteins

2017 ◽  
Vol 56 (45) ◽  
pp. 14020-14024 ◽  
Author(s):  
Nicola Salvi ◽  
Anton Abyzov ◽  
Martin Blackledge
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Nmr Relaxation ◽  
Analytical Description ◽  
Disordered Proteins ◽  
Intrinsically Disordered

Triple resonance 15N NMR relaxation experiments for studies of intrinsically disordered proteins

2017 ◽  
Vol 69 (3) ◽  
pp. 133-146 ◽  
Author(s):  
Pavel Srb ◽  
Jiří Nováček ◽  
Pavel Kadeřávek ◽  
Alžbeta Rabatinová ◽  
Libor Krásný ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Nmr Relaxation ◽  
Disordered Proteins ◽  
15N Nmr ◽  
Triple Resonance ◽  
Intrinsically Disordered ◽  
15N Nmr Relaxation ◽  
Relaxation Experiments

scholarly journals Probing Local Backbone Geometries in Intrinsically Disordered Proteins by Cross-Correlated NMR Relaxation

2013 ◽  
Vol 52 (17) ◽  
pp. 4604-4606 ◽  
Author(s):  
Jan Stanek ◽  
Saurabh Saxena ◽  
Leonhard Geist ◽  
Robert Konrat ◽  
Wiktor Koźmiński
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Nmr Relaxation ◽  
Disordered Proteins ◽  
Intrinsically Disordered

The sequence–ensemble relationship in fuzzy protein complexes

2021 ◽  
Vol 118 (37) ◽  
pp. e2020562118
Author(s):  
San Hadži ◽  
Remy Loris ◽  
Jurij Lah
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Protein Complexes ◽  
Structural Characteristics ◽  
Nmr Relaxation ◽  
Structural Heterogeneity ◽  
Conformational Space ◽  
Disordered Proteins ◽  
Statistical Thermodynamic ◽  
Intrinsically Disordered ◽  
Two Parameters

Intrinsically disordered proteins (IDPs) interact with globular proteins through a variety of mechanisms, resulting in the structurally heterogeneous ensembles known as fuzzy complexes. While there exists a reasonable comprehension on how IDP sequence determines the unbound IDP ensemble, little is known about what shapes the structural characteristics of IDPs bound to their targets. Using a statistical thermodynamic model, we show that the target-bound ensembles are determined by a simple code that combines the IDP sequence and the distribution of IDP–target interaction hotspots. These two parameters define the conformational space of target-bound IDPs and rationalize the observed structural heterogeneity of fuzzy complexes. The presented model successfully reproduces the dynamical signatures of target-bound IDPs from the NMR relaxation experiments as well as the changes of interaction affinity and the IDP helicity induced by mutations. The model explains how the target-bound IDP ensemble adapts to mutations in order to achieve an optimal balance between conformational freedom and interaction energy. Taken together, the presented sequence–ensemble relationship of fuzzy complexes explains the different manifestations of IDP disorder in folding-upon-binding processes.

Interpretation of biomolecular NMR spin relaxation parametersThis paper is one of a selection of papers published in this special issue entitled “Canadian Society of Biochemistry, Molecular & Cellular Biology 52nd Annual Meeting — Protein Folding: Principles and Diseases” and has undergone the Journal's usual peer review process.

2010 ◽  
Vol 88 (2) ◽  
pp. 131-142 ◽  
Author(s):  
Tyler Reddy ◽  
Jan K. Rainey
Keyword(s):  
Spin Relaxation ◽  
Intrinsically Disordered Proteins ◽  
Nmr Relaxation ◽  
Disordered Proteins ◽  
Detailed Model ◽  
Intrinsically Disordered ◽  
Density Mapping ◽  
Model Free ◽  
Relaxation Experiments ◽  
Nmr Spin Relaxation

Biomolecular nuclear magnetic resonance (NMR) spin relaxation experiments provide exquisite information on the picosecond to nanosecond timescale motions of bond vectors. Spin–lattice (T1) and spin–spin (T2) relaxation times and the steady-state nuclear Overhauser effect (NOE) are the first set of parameters extracted from typical 15N or 13C NMR relaxation experiments. Therefore, verifying that T1, T2, and NOE are consistent with theoretical predictions is an important step before carrying out the more detailed model-free and reduced spectral density mapping analyses commonly employed. In this mini-review, we discuss the essential motional parameters used to describe biomolecular dynamics in the context of a variety of examples of folded and intrinsically disordered proteins and peptides in aqueous and membrane mimetic environments. Estimates of these parameters can be used as input for an online interface, introduced herein, allowing plotting of trends of T1, T2, and NOE with magnetic field strength. The plots may serve as a first-check to the spectroscopist preparing to embark on a detailed NMR relaxation analysis.

scholarly journals Structural and Aggregation Features of a Human κ-Casein Fragment with Antitumor and Cell-Penetrating Properties

Molecules ◽  
2019 ◽  
Vol 24 (16) ◽  
pp. 2919 ◽  
Author(s):  
Olga A. Chinak ◽  
Andrey V. Shernyukov ◽  
Sergey S. Ovcherenko ◽  
Evgeniy A. Sviridov ◽  
Victor M. Golyshev ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Intrinsically Disordered Proteins ◽  
Nmr Relaxation ◽  
Disordered Proteins ◽  
Breast Adenocarcinoma ◽  
Amino Acid Residues ◽  
Paramagnetic Resonance ◽  
Proteolytic Fragment ◽  
Intrinsically Disordered ◽  
A Site

Intrinsically disordered proteins play a central role in dynamic regulatory and assembly processes in the cell. Recently, a human κ-casein proteolytic fragment called lactaptin (8.6 kDa) was found to induce apoptosis of human breast adenocarcinoma MCF-7 and MDA-MB-231 cells with no cytotoxic activity toward normal cells. Earlier, we had designed some recombinant analogs of lactaptin and compared their biological activity. Among these analogs, RL2 has the highest antitumor activity, but the amino acid residues and secondary structures that are responsible for RL2′s activity remain unclear. To elucidate the structure–activity relations of RL2, we studied the structural and aggregation features of this fairly large intrinsically disordered fragment of human milk κ-casein by a combination of physicochemical methods: NMR, paramagnetic relaxation enhancement (PRE), Electron Paramagnetic Resonance (EPR), circular dichroism, dynamic light scattering, atomic force microscopy, and a cytotoxic activity assay. It was found that in solution, RL2 exists as stand-alone monomeric particles and large aggregates. Whereas the disulfide-bonded homodimer turned out to be more prone to assembly into large aggregates, the monomer predominantly forms single particles. NMR relaxation analysis of spin-labeled RL2 showed that the RL2 N-terminal region, which is essential not only for multimerization of the peptide but also for its proapoptotic action on cancer cells, is more ordered than its C-terminal counterpart and contains a site with a propensity for α-helical secondary structure.

scholarly journals Dynamics in Natural and Designed Elastins and Their Relation to Elastic Fiber Structure and Recoil

2020 ◽  
Author(s):  
M. F. C. A. Carvajal ◽  
J. M. Preston ◽  
N. M. Jamhawi ◽  
T. M. Sabo ◽  
J. M. Aramini ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Critical Role ◽  
Elastic Fiber ◽  
Hydrophobic Effect ◽  
Nmr Relaxation ◽  
Order Parameters ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Local Ordering ◽  
High Degree

ABSTRACTElastin fibers assemble in the extracellular matrix from the precursor protein tropoelastin and provide the flexibility and spontaneous recoil required for arterial function. Unlike many proteins, a structure-function mechanism for elastin has been elusive. We have performed detailed NMR relaxation studies of the dynamics of the minielastin 24x′ in solution and of purified bovine elastin fibers in the presence and absence of mechanical stress. The low sequence complexity of 24x′ enables us to determine dynamical timescales and degrees of local ordering with residue-specific resolution in the cross-link and hydrophobic modules using NMR relaxation. We find an extremely high degree of disorder, with order parameters for the entirety of the hydrophobic domains near zero, resembling that of simple chemical polymers and less than the order parameters that have been observed in other intrinsically disordered proteins. We find that backbone order parameters in natural, purified elastin fibers are comparable to those found in 24x′ in solution. The difference in dynamics, compared to 24x′, is that backbone correlation times are significantly slowed in purified elastin. Moreover, when elastin is mechanically stretched, the high chain disorder in purified elastin is retained - showing that any change in local ordering is below that detectable in our experiment. Combined with our previous finding of a 10-fold increase in the ordering of water when fully hydrated elastin fibers are stretched by 50%, these results support the hypothesis that stretch induced solvent ordering, i.e. the hydrophobic effect, is a key player in the elastic recoil of elastin.SIGNIFICANCEElastin is responsible for the spontaneous recoil of atrial walls that is necessary for cardiovascular function. Despite this critical role, the mechanism driving entropic recoil has remained unclear. Elastin is unusual in that it is intrinsically disordered in both soluble and fibrous forms. Using NMR, we have determined the timescales and amplitudes of dynamics in a soluble elastin mimetic and in cross-linked elastin in both relaxed and stretched states. Although dynamical timescales are different, both the soluble elastin mimetic and fibrillar elastin display an exceptionally high degree of disorder. No detectable increase in protein ordering was observed upon stretching, suggesting that entropic recoil is primarily driven by the hydrophobic effect and not configurational entropy loss.

scholarly journals Solvent-dependent segmental dynamics in intrinsically disordered proteins

2019 ◽  
Vol 5 (6) ◽  
pp. eaax2348 ◽  
Author(s):  
Nicola Salvi ◽  
Anton Abyzov ◽  
Martin Blackledge
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Dynamic Properties ◽  
Nmr Relaxation ◽  
Bulk Water ◽  
Water Dynamics ◽  
Disordered Proteins ◽  
Segmental Dynamics ◽  
Intrinsically Disordered ◽  
Dynamics Simulations ◽  
And Function

Protein and water dynamics have a synergistic relationship, which is particularly important for intrinsically disordered proteins (IDPs), although the details of this coupling remain poorly understood. Here, we combine temperature-dependent molecular dynamics simulations using different water models with extensive nuclear magnetic resonance (NMR) relaxation to examine the importance of distinct modes of solvent and solute motion for the accurate reproduction of site-specific dynamics in IDPs. We find that water dynamics play a key role in motional processes internal to “segments” of IDPs, stretches of primary sequence that share dynamic properties and behave as discrete dynamic units. We identify a relationship between the time scales of intrasegment dynamics and the lifetime of hydrogen bonds in bulk water. Correct description of these motions is essential for accurate reproduction of protein relaxation. Our findings open important perspectives for understanding the role of hydration water on the behavior and function of IDPs in solution.

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