scholarly journals Molecular Swiss Army Knives: Tardigrade CAHS Proteins Mediate Desiccation Tolerance Through Multiple Mechanisms

2021 ◽  
Author(s):  
Cherie S. Hesgrove ◽  
Kenny H. Nguyen ◽  
Sourav Biswas ◽  
Charles A. Childs ◽  
Shraddha KC ◽  
...  
Keyword(s):  
Robust Stabilization ◽  
Intrinsically Disordered Protein ◽  
Residual Water ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Animal Physiology ◽  
Gel Phase ◽  
Water Bears

Tardigrades, also known as water bears, make up a phylum of small but extremely robust animals renowned for their ability to survive extreme stresses including desiccation. How tardigrades survive desiccation is one of the enduring mysteries of animal physiology. Here we show that CAHS D, an intrinsically disordered protein belonging to a unique family of proteins possessed only by tardigrades, undergoes a liquid-to-gel phase transition in a concentration dependent manner. Unlike other gelling proteins such as gelatin, our data support a mechanism in which gelation of CAHS D is driven by intermolecular beta-beta interactions. We find that gelation of CAHS D promotes the slowing of diffusion, and coordination of residual water. Slowed diffusion and increased water coordination correlate with the ability of CAHS D to provide robust stabilization of an enzyme, lactate dehydrogenase, which otherwise unfolds when dried. Conversely, slowed diffusion and water coordination do not promote the prevention of protein aggregation during drying. Our study demonstrates that distinct mechanisms are required for holistic protection during desiccation, and that protectants, such as CAHS D, can act as "molecular Swiss army knives" capable of providing protection through several different mechanisms simultaneously.

scholarly journals Intrinsically disordered protein RBM14 plays a role in generation of RNA:DNA hybrids at double-strand break sites

2020 ◽  
Vol 117 (10) ◽  
pp. 5329-5338 ◽  
Author(s):  
Yumi Jang ◽  
Zeinab Elsayed ◽  
Rebeka Eki ◽  
Shuaixin He ◽  
Kang-Ping Du ◽  
...  
Keyword(s):  
Dna Damage ◽  
Rna Polymerase Ii ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Intrinsically Disordered Protein ◽  
Strand Break ◽  
Dependent Manner ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Rna:Dna Hybrids

Accumulating evidence suggests participation of RNA-binding proteins with intrinsically disordered domains (IDPs) in the DNA damage response (DDR). These IDPs form liquid compartments at DNA damage sites in a poly(ADP ribose) (PAR)-dependent manner. However, it is greatly unknown how the IDPs are involved in DDR. We have shown previously that one of the IDPs RBM14 is required for the canonical nonhomologous end joining (cNHEJ). Here we show that RBM14 is recruited to DNA damage sites in a PARP- and RNA polymerase II (RNAPII)-dependent manner. Both KU and RBM14 are required for RNAPII-dependent generation of RNA:DNA hybrids at DNA damage sites. In fact, RBM14 binds to RNA:DNA hybrids. Furthermore, RNA:DNA hybrids and RNAPII are detected at gene-coding as well as at intergenic areas when double-strand breaks (DSBs) are induced. We propose that the cNHEJ pathway utilizes damage-induced transcription and intrinsically disordered protein RBM14 for efficient repair of DSBs.

scholarly journals The Non-Fibrillating N-Terminal of α-Synuclein Binds and Co-Fibrillates with Heparin

Biomolecules ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1192
Author(s):  
Line K. Skaanning ◽  
Angelo Santoro ◽  
Thomas Skamris ◽  
Jacob Hertz Martinsen ◽  
Anna Maria D’Ursi ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Structural Changes ◽  
Lewy Bodies ◽  
Intrinsically Disordered Protein ◽  
Molar Ratio ◽  
Type I ◽  
Dependent Manner ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Main Component

The intrinsically disordered protein α-synuclein (aSN) is, in its fibrillated state, the main component of Lewy bodies—hallmarks of Parkinson’s disease. Additional Lewy body components include glycosaminoglycans, including heparan sulfate proteoglycans. In humans, heparan sulfate has, in an age-dependent manner, shown increased levels of sulfation. Heparin, a highly sulfated glycosaminoglycan, is a relevant mimic for mature heparan sulfate and has been shown to influence aSN fibrillation. Here, we decompose the underlying properties of the interaction between heparin and aSN and the effect of heparin on fibrillation. Via the isolation of the first 61 residues of aSN, which lacked intrinsic fibrillation propensity, fibrillation could be induced by heparin, and access to the initial steps in fibrillation was possible. Here, structural changes with shifts from disorder via type I β-turns to β-sheets were revealed, correlating with an increase in the aSN1–61/heparin molar ratio. Fluorescence microscopy revealed that heparin and aSN1–61 co-exist in the final fibrils. We conclude that heparin can induce the fibrillation of aSN1–61, through binding to the N-terminal with an affinity that is higher in the truncated form of aSN. It does so by specifically modulating the structure of aSN via the formation of type I β-turn structures likely critical for triggering aSN fibrillation.

Self-Assembling Micelles Based on an Intrinsically Disordered Protein Domain

2018 ◽  
Author(s):  
Sarah Klass ◽  
Matthew J. Smith ◽  
Tahoe Fiala ◽  
Jessica Lee ◽  
Anthony Omole ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Fusion Proteins ◽  
Organic Molecules ◽  
Intrinsically Disordered Protein ◽  
Protein Domain ◽  
Enzymatic Cleavage ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Self Assembling ◽  
Protein Tag

Herein, we describe a new series of fusion proteins that have been developed to self-assemble spontaneously into stable micelles that are 27 nm in diameter after enzymatic cleavage of a solubilizing protein tag. The sequences of the proteins are based on a human intrinsically disordered protein, which has been appended with a hydrophobic segment. The micelles were found to form across a broad range of pH, ionic strength, and temperature conditions, with critical micelle concentration (CMC) values below 1 µM being observed in some cases. The reported micelles were found to solubilize hydrophobic metal complexes and organic molecules, suggesting their potential suitability for catalysis and drug delivery applications.

scholarly journals Mutations of Intrinsically Disordered Protein Regions Can Drive Cancer but Lack Therapeutic Strategies

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 381
Author(s):  
Bálint Mészáros ◽  
Borbála Hajdu-Soltész ◽  
András Zeke ◽  
Zsuzsanna Dosztányi
Keyword(s):  
Gene Expression Regulation ◽  
Treatment Options ◽  
Intrinsically Disordered Protein ◽  
System Level ◽  
Alternative Mechanism ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Disordered Protein ◽  
Cancer Types ◽  
Cancer Drivers

Many proteins contain intrinsically disordered regions (IDRs) which carry out important functions without relying on a single well-defined conformation. IDRs are increasingly recognized as critical elements of regulatory networks and have been also associated with cancer. However, it is unknown whether mutations targeting IDRs represent a distinct class of driver events associated with specific molecular and system-level properties, cancer types and treatment options. Here, we used an integrative computational approach to explore the direct role of intrinsically disordered protein regions driving cancer. We showed that around 20% of cancer drivers are primarily targeted through a disordered region. These IDRs can function in multiple ways which are distinct from the functional mechanisms of ordered drivers. Disordered drivers play a central role in context-dependent interaction networks and are enriched in specific biological processes such as transcription, gene expression regulation and protein degradation. Furthermore, their modulation represents an alternative mechanism for the emergence of all known cancer hallmarks. Importantly, in certain cancer patients, mutations of disordered drivers represent key driving events. However, treatment options for such patients are currently severely limited. The presented study highlights a largely overlooked class of cancer drivers associated with specific cancer types that need novel therapeutic options.

scholarly journals Mediator subunit Med15 dictates the conserved “fuzzy” binding mechanism of yeast transcription activators Gal4 and Gcn4

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lisa M. Tuttle ◽  
Derek Pacheco ◽  
Linda Warfield ◽  
Damien B. Wilburn ◽  
Steven Hahn ◽  
...  
Keyword(s):  
Intrinsically Disordered Protein ◽  
Activation Function ◽  
Binding Mechanism ◽  
Binding Partner ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Independent Mechanism ◽  
Transcription Activators ◽  
Common Sequence

AbstractThe acidic activation domain (AD) of yeast transcription factor Gal4 plays a dual role in transcription repression and activation through binding to Gal80 repressor and Mediator subunit Med15. The activation function of Gal4 arises from two hydrophobic regions within the 40-residue AD. We show by NMR that each AD region binds the Mediator subunit Med15 using a “fuzzy” protein interface. Remarkably, comparison of chemical shift perturbations shows that Gal4 and Gcn4, two intrinsically disordered ADs of different sequence, interact nearly identically with Med15. The finding that two ADs of different sequence use an identical fuzzy binding mechanism shows a common sequence-independent mechanism for AD-Mediator binding, similar to interactions within a hydrophobic cloud. In contrast, the same region of Gal4 AD interacts strongly with Gal80 via a distinct structured complex, implying that the structured binding partner of an intrinsically disordered protein dictates the type of protein–protein interaction.

scholarly journals Biomorphs: Complex Morphogenesis by a Model Intrinsically Disordered Protein (Small 51/2020)

Small ◽  
2020 ◽  
Vol 16 (51) ◽  
pp. 2070276
Author(s):  
Constancio González‐Obeso ◽  
Miguel González‐Pérez ◽  
João F. Mano ◽  
Matilde Alonso ◽  
José Carlos Rodríguez‐Cabello
Keyword(s):  
Intrinsically Disordered Protein ◽  
Intrinsically Disordered ◽  
Disordered Protein
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