NMR Spectroscopic Studies of Intrinsically Disordered Proteins at Near-Physiological Conditions

2013 ◽  
Vol 52 (45) ◽  
pp. 11808-11812 ◽  
Author(s):  
Sergio Gil ◽  
Tomáš Hošek ◽  
Zsofia Solyom ◽  
Rainer Kümmerle ◽  
Bernhard Brutscher ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Spectroscopic Studies ◽  
Disordered Proteins ◽  
Physiological Conditions ◽  
Intrinsically Disordered

NMR Spectroscopic Studies of Intrinsically Disordered Proteins at Near-Physiological Conditions

2013 ◽  
Vol 125 (45) ◽  
pp. 12024-12028 ◽  
Author(s):  
Sergio Gil ◽  
Tomáš Hošek ◽  
Zsofia Solyom ◽  
Rainer Kümmerle ◽  
Bernhard Brutscher ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Spectroscopic Studies ◽  
Disordered Proteins ◽  
Physiological Conditions ◽  
Intrinsically Disordered

scholarly journals Intrinsically Disordered Proteins in Chronic Diseases

Biomolecules ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 147 ◽  
Author(s):  
Prakash Kulkarni ◽  
Vladimir Uversky
Keyword(s):  
Chronic Diseases ◽  
Intrinsically Disordered Proteins ◽  
Large Fraction ◽  
3D Structure ◽  
Human Proteome ◽  
Disordered Proteins ◽  
3D Structures ◽  
Physiological Conditions ◽  
Intrinsically Disordered

It is now increasingly evident that a large fraction of the human proteome comprises proteins that, under physiological conditions, lack fixed, ordered 3D structures as a whole or have segments that are not likely to form a defined 3D structure [...]

scholarly journals The Interaction of Alpha-synuclein with Membranes and its Implication in Parkinson's Disease: A Literature Review

2015 ◽  
Vol 10 (10) ◽  
pp. 1934578X1501001
Author(s):  
Azucena Gonzalez-Horta
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Membrane Structure ◽  
Intrinsically Disordered Proteins ◽  
Alpha Synuclein ◽  
Disordered Proteins ◽  
Physiological Conditions ◽  
Intrinsically Disordered ◽  
Fluorescence Techniques ◽  
Folded Structure

Alpha-synuclein belongs to the class of intrinsically disordered proteins lacking a well-folded structure under physiological conditions. The conversion of alpha-synuclein from a soluble monomer to an insoluble fibril may underlie the neurodegeneration associated with Parkinson's disease (PD). Although the exact mechanism of alpha-synuclein toxicity is still unknown, it has been proposed that alpha-synuclein disturbs membrane structure, leading to increased membrane permeability and eventual cell death. This review highlights the significant role played by fluorescence techniques in unraveling the nature of interactions between alpha-synuclein and membranes and its implications in PD.

Sequence Specificity Despite Intrinsic Disorder: How a Disease-Associated Val/Met Polymorphism Shifts Tertiary Interactions in a Long Disordered Protein

2019 ◽  
Author(s):  
Ruchi Lohia ◽  
Reza Salari ◽  
Grace Brannigan
Keyword(s):  
Secondary Structure ◽  
Electrostatic Interactions ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Sequence Specificity ◽  
Intrinsically Disordered ◽  
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>

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