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.

scholarly journals Clustering of human prion protein and α-synuclein oligomers requires the prion protein N-terminus

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Nadine S. Rösener ◽  
Lothar Gremer ◽  
Michael M. Wördehoff ◽  
Tatsiana Kupreichyk ◽  
Manuel Etzkorn ◽  
...  
Keyword(s):  
Prion Protein ◽  
Amyloid Β ◽  
Intrinsically Disordered Protein ◽  
Molar Ratio ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
N Terminus ◽  
Human Prion Protein ◽  
Intrinsically Disordered Protein Region ◽  
Slow Dissociation

AbstractThe interaction of prion protein (PrP) and α-synuclein (αSyn) oligomers causes synaptic impairment that might trigger Parkinson’s disease and other synucleinopathies. Here, we report that αSyn oligomers (αSynO) cluster with human PrP (huPrP) into micron-sized condensates. Multivalency of αSyn within oligomers is required for condensation, since clustering with huPrP is not observed for monomeric αSyn. The stoichiometry of the heteroassemblies is well defined with an αSyn:huPrP molar ratio of about 1:1. The αSynO−huPrP interaction is of high affinity, signified by slow dissociation. The huPrP region responsible for condensation of αSynO, residues 95−111 in the intrinsically disordered N-terminus, corresponds to the region required for αSynO-mediated cognitive impairment. HuPrP, moreover, achieves co-clustering of αSynO and Alzheimer’s disease-associated amyloid-β oligomers, providing a case of a cross-interaction of two amyloidogenic proteins through an interlinking intrinsically disordered protein region. The results suggest that αSynO-mediated condensation of huPrP is involved in the pathogenesis of synucleinopathies.

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 Zinc induced structural changes in the intrinsically disordered BDNF Met prodomain confer synaptic elimination

Metallomics ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 1208-1219 ◽  
Author(s):  
Jing Wang ◽  
Agustin Anastasia ◽  
Henrietta Bains ◽  
Joanna I. Giza ◽  
David G. Clossey ◽  
...  
Keyword(s):  
Human Brain ◽  
Neurotrophic Factor ◽  
Structural Changes ◽  
Intrinsically Disordered Protein ◽  
Brain Derived Neurotrophic Factor ◽  
Protein Product ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Mature Domain

Human brain derived neurotrophic factor (BDNF) encodes a protein product consisting of a C-terminal mature domain (mature BDNF) and an N-terminal prodomain, which is an intrinsically disordered protein.

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 Structural basis of synaptic vesicle assembly promoted by α-synuclein

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Giuliana Fusco ◽  
Tillmann Pape ◽  
Amberley D. Stephens ◽  
Pierre Mahou ◽  
Ana Rita Costa ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Synaptic Vesicle ◽  
Synaptic Vesicles ◽  
Lewy Bodies ◽  
Intrinsically Disordered Protein ◽  
Structural Basis ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Familial Parkinson’S Disease

Abstractα-synuclein (αS) is an intrinsically disordered protein whose fibrillar aggregates are the major constituents of Lewy bodies in Parkinson’s disease. Although the specific function of αS is still unclear, a general consensus is forming that it has a key role in regulating the process of neurotransmitter release, which is associated with the mediation of synaptic vesicle interactions and assembly. Here we report the analysis of wild-type αS and two mutational variants linked to familial Parkinson’s disease to describe the structural basis of a molecular mechanism enabling αS to induce the clustering of synaptic vesicles. We provide support for this ‘double-anchor’ mechanism by rationally designing and experimentally testing a further mutational variant of αS engineered to promote stronger interactions between synaptic vesicles. Our results characterize the nature of the active conformations of αS that mediate the clustering of synaptic vesicles, and indicate their relevance in both functional and pathological contexts.

Monitoring structural changes in intrinsically disordered proteins using QCM-D: application to the bacterial cell division protein ZipA

2016 ◽  
Vol 52 (39) ◽  
pp. 6541-6544 ◽  
Author(s):  
Pablo Mateos-Gil ◽  
Achilleas Tsortos ◽  
Marisela Vélez ◽  
Electra Gizeli
Keyword(s):  
Cell Division ◽  
Structural Changes ◽  
Intrinsically Disordered Proteins ◽  
Intrinsically Disordered Protein ◽  
Disordered Proteins ◽  
Bacterial Cell Division ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Cell Division Protein

Characterization of structural changes in an intrinsically disordered protein attached on a QCM-D, with a sensitivity of 1.8 nm or better.

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.

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