Transient Local Secondary Structure in the Intrinsically Disordered C-Term of the Albino3 Insertase

Disordered Proteins ◽

Sequence Specificity ◽

Specific Effects ◽

Heterogeneous Polymer ◽

Non Local ◽

Dynamics Simulations

<div>The role of electrostatic interactions and mutations that change charge states in intrinsically disordered proteins (IDPs) is well-established, but many disease-associated mutations in IDPs are charge-neutral. The Val66Met single nucleotide polymorphism (SNP) encodes a hydrophobic-to-hydrophobic mutation at the midpoint of the prodomain of precursor brain-derived neurotrophic factor (BDNF), one of the earliest SNPs to be associated with neuropsychiatric disorders, for which the underlying molecular mechanism is unknown. Here we report on over 250 μs of fully-atomistic, explicit solvent, temperature replica exchange molecular dynamics simulations of the 91 residue BDNF prodomain, for both the V66 and M66 sequence.</div><div>The simulations were able to correctly reproduce the location of both local and non-local secondary changes due to the Val66Met mutation when compared with NMR spectroscopy. We find that the local structure change is mediated via entropic and sequence specific effects. We show that the highly disordered prodomain can be meaningfully divided into domains based on sequence alone. Monte Carlo simulations of a self-excluding heterogeneous polymer, with monomers representing each domain, suggest the sequence would be effectively segmented by the long, highly disordered polyampholyte near the sequence midpoint. This is qualitatively consistent with observed interdomain contacts within the BDNF prodomain, although contacts between the two segments are enriched relative to the self-excluding polymer. The Val66Met mutation increases interactions across the boundary between the two segments, due in part to a specific Met-Met interaction with a Methionine in the other segment. This effect propagates to cause the non-local change in secondary structure around the second methionine, previously observed in NMR. The effect is not mediated simply via changes in inter-domain contacts but is also dependent on secondary structure formation around residue 66, indicating a mechanism for secondary structure coupling in disordered proteins. </div>

Interactions of intrinsically disordered Thellungiella salsuginea dehydrins TsDHN-1 and TsDHN-2 with membranes — synergistic effects of lipid composition and temperature on secondary structure

Biochemistry and Cell Biology ◽

10.1139/o10-026 ◽

2010 ◽

Vol 88 (5) ◽

pp. 791-807 ◽

Cited By ~ 35

Author(s):

Luna N. Rahman ◽

Lin Chen ◽

Sumaiya Nazim ◽

Vladimir V. Bamm ◽

Mahmoud W. Yaish ◽

...

Keyword(s):

Secondary Structure ◽

Synergistic Effects ◽

Yukon Territory ◽

Membrane Structures ◽

Thellungiella Salsuginea ◽

Induced Folding ◽

Large Unilamellar Vesicles ◽

Unstructured Proteins ◽

Extreme Cold

Dehydrins are intrinsically disordered (unstructured) proteins that are expressed in plants experiencing stressful conditions such as drought or low temperature. Dehydrins are typically found in the cytosol and nucleus, but also associate with chloroplasts, mitochondria, and the plasma membrane. Although their role is not completely understood, it has been suggested that they stabilize proteins or membrane structures during environmental stress, the latter association mediated by formation of amphipathic α-helices by conserved regions called the K-segments. Thellungiella salsuginea is a crucifer that thrives in the Canadian sub-Arctic (Yukon Territory) where it grows on saline-rich soils and experiences periods of both extreme cold and drought. We have cloned and expressed in Escherichia coli two dehydrins from this plant, denoted TsDHN-1 (acidic) and TsDHN-2 (basic). Here, we show using transmission-Fourier transform infrared (FTIR) spectroscopy that ordered secondary structure is induced and stabilized in these proteins by association with large unilamellar vesicles emulating the lipid compositions of plant plasma and organellar membranes. Moreover, this induced folding is enhanced at low temperatures, lending credence to the hypothesis that dehydrins stabilize plant outer and organellar membranes in conditions of cold.

An Evolutionary Algorithm for the Design of Different Degrees of Secondary Structure in Intrinsically Disordered Proteins (IDPs)

Biophysical Journal ◽

10.1016/j.bpj.2014.11.1259 ◽

2015 ◽

Vol 108 (2) ◽

pp. 228a ◽

Cited By ~ 1

Author(s):

Tyler S. Harmon ◽

Rohit V. Pappu

Keyword(s):

Secondary Structure ◽

Evolutionary Algorithm ◽

Disordered Proteins ◽

Intrinsically Disordered

WT and A53T α-synuclein systems: Melting Diagram and its new interpretation

10.1101/724922 ◽

2019 ◽

Author(s):

M. Bokor ◽

Á. Tantos ◽

P. Tompa ◽

K.-H. Han ◽

K. Tompa

Keyword(s):

Secondary Structure ◽

Structural Disorder ◽

Water Molecules ◽

Hydration Water ◽

Wild Type ◽

Water Binding ◽

Potential Barriers ◽

Mobile Water ◽

Binding Interfaces

AbstractParkinson’s disease is connected with abnormal α-synuclein (αS) aggregation. Energetics of potential barriers governing motions of hydration water is examined. Information about the distributions and heights of potential barriers is gained by a thermodynamical approach. The ratios of the heterogeneous water-binding interfaces measure proteins’ structural disorder. All αS forms possess secondary structural elements though they are intrinsically disordered. Monomers are functional at the lowest potential barriers, where mobile hydration water exists, with monolayer coverage of mobile hydration. The αS monomer contains 33% secondary structure and is more compact than a random coil. A53T αS monomer has a more open structure than the wild type. Monomers realize all possible hydrogen bonds. Half of the mobile hydration water amount for monomers is missing in αS oligomers and αS amyloids. Oligomers are ordered by 66%. Mobile water molecules in the first hydration shell of amyloids are the weakest bound compared to other forms. Wild type and A53T amyloids show identical, low-level hydration, and are considered as disordered to 75%.Statement of SignificanceAggregation of α-synuclein into oligomers, amyloid fibrils is a hallmark of Parkinson’s disease. A thermodynamic approach provides information on the heterogeneity of protein-water bonds in the wild type and A53T mutant monomers, oligomers, amyloids. This information can be related to ratios of heterogeneous water-binding interfaces, which measure the proteins’ structural disorder. Both α-synuclein monomers are intrinsically disordered. The monomers nevertheless have 33% secondary structure. They are functional as long as mobile water molecules surround them. They realize every possible H-bonds with water. Oligomers are like globular proteins with 66% ordered structure. Amyloids are disordered to 75% and are poorly hydrated with loosely bound water. Their hydration is identical. Oligomers, amyloids have only half as much hydrating mobile water as monomers.

Prediction of folding transition-state position (βT) of small, two-state proteins from local secondary structure content

Proteins Structure Function and Bioinformatics ◽

10.1002/prot.21411 ◽

2007 ◽

Vol 68 (1) ◽

pp. 218-222 ◽

Cited By ~ 7

Author(s):

Ji-Tao Huang ◽

Jin-Pei Cheng

Keyword(s):

Secondary Structure ◽

Transition State ◽

Secondary Structure Content ◽

Local Secondary Structure ◽

State Position

Random coil chemical shifts for serine, threonine and tyrosine phosphorylation over a broad pH range

Journal of Biomolecular NMR ◽

10.1007/s10858-019-00283-z ◽

2019 ◽

Vol 73 (12) ◽

pp. 713-725 ◽

Cited By ~ 4

Author(s):

Ruth Hendus-Altenburger ◽

Catarina B. Fernandes ◽

Katrine Bugge ◽

Micha B. A. Kunze ◽

Wouter Boomsma ◽

...

Keyword(s):

Chemical Shift ◽

Secondary Structure ◽

Chemical Shifts ◽

Random Coil ◽

Disordered Proteins ◽

Phosphoryl Group ◽

Intrinsically Disordered Regions ◽

Secondary Chemical

Abstract Phosphorylation is one of the main regulators of cellular signaling typically occurring in flexible parts of folded proteins and in intrinsically disordered regions. It can have distinct effects on the chemical environment as well as on the structural properties near the modification site. Secondary chemical shift analysis is the main NMR method for detection of transiently formed secondary structure in intrinsically disordered proteins (IDPs) and the reliability of the analysis depends on an appropriate choice of random coil model. Random coil chemical shifts and sequence correction factors were previously determined for an Ac-QQXQQ-NH2-peptide series with X being any of the 20 common amino acids. However, a matching dataset on the phosphorylated states has so far only been incompletely determined or determined only at a single pH value. Here we extend the database by the addition of the random coil chemical shifts of the phosphorylated states of serine, threonine and tyrosine measured over a range of pH values covering the pKas of the phosphates and at several temperatures (www.bio.ku.dk/sbinlab/randomcoil). The combined results allow for accurate random coil chemical shift determination of phosphorylated regions at any pH and temperature, minimizing systematic biases of the secondary chemical shifts. Comparison of chemical shifts using random coil sets with and without inclusion of the phosphoryl group, revealed under/over estimations of helicity of up to 33%. The expanded set of random coil values will improve the reliability in detection and quantification of transient secondary structure in phosphorylation-modified IDPs.

Sequence Versus Composition: What Prescribes IDP Biophysical Properties?

Entropy ◽

10.3390/e21070654 ◽

2019 ◽

Vol 21 (7) ◽

pp. 654 ◽

Cited By ~ 2

Author(s):

Jiří Vymětal ◽

Jiří Vondrášek ◽

Klára Hlouchová

Keyword(s):

Amino Acid ◽

Secondary Structure ◽

Random Sequence ◽

Bioinformatic Analysis ◽

Globular Proteins ◽

Disordered Proteins ◽

Compositional Bias ◽

Sequence Versus

Intrinsically disordered proteins (IDPs) represent a distinct class of proteins and are distinguished from globular proteins by conformational plasticity, high evolvability and a broad functional repertoire. Some of their properties are reminiscent of early proteins, but their abundance in eukaryotes, functional properties and compositional bias suggest that IDPs appeared at later evolutionary stages. The spectrum of IDP properties and their determinants are still not well defined. This study compares rudimentary physicochemical properties of IDPs and globular proteins using bioinformatic analysis on the level of their native sequences and random sequence permutations, addressing the contributions of composition versus sequence as determinants of the properties. IDPs have, on average, lower predicted secondary structure contents and aggregation propensities and biased amino acid compositions. However, our study shows that IDPs exhibit a broad range of these properties. Induced fold IDPs exhibit very similar compositions and secondary structure/aggregation propensities to globular proteins, and can be distinguished from unfoldable IDPs based on analysis of these sequence properties. While amino acid composition seems to be a major determinant of aggregation and secondary structure propensities, sequence randomization does not result in dramatic changes to these properties, but for both IDPs and globular proteins seems to fine-tune the tradeoff between folding and aggregation.

Avoiding Regions Symptomatic of Conformational and Functional Flexibility to Identify Antiviral Targets in Current and Future Coronaviruses

Genome Biology and Evolution ◽

10.1093/gbe/evw246 ◽

2016 ◽

Vol 8 (11) ◽

pp. 3471-3484 ◽

Cited By ~ 5

Author(s):

Jordon Rahaman ◽

Jessica Siltberg-Liberles

Keyword(s):

Secondary Structure ◽

Structure Prediction ◽

Secondary Structure Prediction ◽

Nonstructural Protein ◽

Intrinsic Disorder ◽

Sequence Motif ◽

Protein Families ◽

Intrinsically Disordered Regions ◽

Antiviral Targets

Abstract Within the last 15 years, two related coronaviruses (Severe Acute Respiratory Syndrome [SARS]-CoV and Middle East Respiratory Syndrome [MERS]-CoV) expanded their host range to include humans, with increased virulence in their new host. Coronaviruses were recently found to have little intrinsic disorder compared with many other virus families. Because intrinsically disordered regions have been proposed to be important for rewiring interactions between virus and host, we investigated the conservation of intrinsic disorder and secondary structure in coronaviruses in an evolutionary context. We found that regions of intrinsic disorder are rarely conserved among different coronavirus protein families, with the primary exception of the nucleocapsid. Also, secondary structure predictions are only conserved across 50–80% of sites for most protein families, with the implication that 20–50% of sites do not have conserved secondary structure prediction. Furthermore, nonconserved structure sites are significantly less constrained in sequence divergence than either sites conserved in the secondary structure or sites conserved in loop. Avoiding regions symptomatic of conformational flexibility such as disordered sites and sites with nonconserved secondary structure to identify potential broad-specificity antiviral targets, only one sequence motif (five residues or longer) remains from the >10,000 starting sites across all coronaviruses in this study. The identified sequence motif is found within the nonstructural protein (NSP) 12 and constitutes an antiviral target potentially effective against the present day and future coronaviruses. On shorter evolutionary timescales, the SARS and MERS clades have more sequence motifs fulfilling the criteria applied. Interestingly, many motifs map to NSP12 making this a prime target for coronavirus antivirals.