scholarly journals Structure and Dynamics of an Intrinsically Disordered Protein Region That Partially Folds upon Binding by Chemical-Exchange NMR

2017 ◽  
Vol 139 (35) ◽  
pp. 12219-12227 ◽  
Author(s):  
Cyril Charlier ◽  
Guillaume Bouvignies ◽  
Philippe Pelupessy ◽  
Astrid Walrant ◽  
Rodrigue Marquant ◽  
...  
Keyword(s):  
Chemical Exchange ◽  
Intrinsically Disordered Protein ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Structure And Dynamics ◽  
Intrinsically Disordered Protein Region

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.

The human disease gene CLEC16A encodes an intrinsically disordered protein region required for mitochondrial quality control

2021 ◽  
Author(s):  
Morgan A. Gingerich ◽  
Xueying Liu ◽  
Biaoxin Chai ◽  
Gemma L. Pearson ◽  
Michael P. Vincent ◽  
...  
Keyword(s):  
Quality Control ◽  
Human Disease ◽  
Intrinsically Disordered Protein ◽  
Mitochondrial Quality Control ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Functional Regions ◽  
C Terminus ◽  
Intrinsically Disordered Protein Region

CLEC16A regulates mitochondrial health through mitophagy and is associated with over 20 human diseases. While CLEC16A has ubiquitin ligase activity, the key structural and functional regions of CLEC16A, and their relevance for human disease, remain unknown. Here, we report that a disease-associated CLEC16A variant lacks a C-terminal intrinsically disordered protein region (IDPR) that is critical for mitochondrial quality control. Using carbon detect NMR, we find that the CLEC16A C terminus lacks secondary structure, validating the presence of an IDPR. Loss of the CLEC16A C-terminal IDPR in vivo impairs pancreatic β-cell mitophagy, mitochondrial function, and glucose-stimulated insulin secretion, ultimately causing glucose intolerance. Deletion of the CLEC16A C-terminal IDPR increases its self-ubiquitination and destabilizes CLEC16A, thus impairing formation of a critical CLEC16A-dependent mitophagy complex. Importantly, CLEC16A stability is dependent on proline bias within the C-terminal IDPR, but not amino acid sequence order or charge. Together, we clarify how an IDPR in CLEC16A prevents diabetes, thus implicating the disruption of IDPRs as novel pathological contributors to diabetes and other CLEC16A-associated diseases.

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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