Related ArticlesPolyglutamine amyloid core boundaries and flanking domain dynamics in huntingtin fragment fibrils determined by solid-state NMR.
Biochemistry. 2014 Oct 3;
Authors: Hoop CL, Lin HK, Kar K, Hou Z, Poirier MA, Wetzel R, van der Wel PC
Abstract
In Huntington's Disease (HD), expansion of a polyglutamine (polyQ) domain in the huntingtin (htt) protein leads to misfolding and aggregation. There is much interest in the molecular features that distinguish monomeric, oligomeric, and fibrillar species that populate the aggregation pathway and likely differ in cytotoxicity. The mechanism and rate of aggregation are greatly affected by the domains flanking the polyQ segment within the exon 1 of htt. A "protective" C-terminal proline-rich flanking domain inhibits aggregation by inducing polyproline II structure (PPII) within an extended portion of polyQ. The N-terminal flanking segment (htt(NT)) adopts an ?-helical structure as it drives aggregation, helps stabilize oligomers and fibrils, and is seemingly integral to their supramolecular assembly. Via solid-state NMR (ssNMR) we probe how, in the mature fibrils, the htt flanking domains impact the polyQ domain, and in particular the localization of the ?-structured amyloid core. Using residue-specific and uniformly labeled samples, we find that the amyloid core occupies most of the polyQ domain, but ends just prior to the prolines. We probe the structural and dynamical features of the remarkably abrupt ?-sheet to PPII transition, and discuss the potential connections to certain htt-binding proteins. We also examine the htt(NT) ?-helix outside the polyQ amyloid core. Despite its presumed structural and demonstrated stabilizing roles in the fibrils, quantitative ssNMR measurements of residue-specific dynamics show that it undergoes distinct solvent-coupled motion. This dynamical feature seems reminiscent of molten-globule-like ?-helix-rich features attributed to the non-fibrillar oligomeric species of various amyloidogenic proteins.
PMID: 25280367 [PubMed - as supplied by publisher]
[NMR paper] Solid-state NMR sequential assignments of the amyloid core of full-length Sup35p.
Solid-state NMR sequential assignments of the amyloid core of full-length Sup35p.
Solid-state NMR sequential assignments of the amyloid core of full-length Sup35p.
Biomol NMR Assign. 2013 Aug 14;
Authors: Schütz AK, Habenstein B, Luckgei N, Bousset L, Sourigues Y, Nielsen AB, Melki R, Böckmann A, Meier BH
Abstract
Sup35p is a yeast prion and is responsible for the trait in Saccharomyces cerevisiae. With 685 amino acids, full-length soluble and fibrillar Sup35p are challenging targets for structural biology as they cannot be investigated...
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08-15-2013 07:45 PM
[NMR paper] Solid-state NMR sequential assignments of the amyloid core of Sup35pNM.
Solid-state NMR sequential assignments of the amyloid core of Sup35pNM.
Solid-state NMR sequential assignments of the amyloid core of Sup35pNM.
Biomol NMR Assign. 2013 Aug 10;
Authors: Luckgei N, Schütz AK, Habenstein B, Bousset L, Sourigues Y, Melki R, Meier BH, Böckmann A
Abstract
Sup35pNM represents the N-terminal and middle (M) domains of the yeast Saccharomyces cerevisiae prion Sup35p. This fragment is commonly used for structural and functional studies of Sup35p. We here present a solid-state NMR study of fibrils formed by this...
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08-13-2013 04:26 PM
[NMR paper] Advanced Solid-State NMR Approaches for Structure Determination of Membrane Proteins and Amyloid Fibrils.
Advanced Solid-State NMR Approaches for Structure Determination of Membrane Proteins and Amyloid Fibrils.
Advanced Solid-State NMR Approaches for Structure Determination of Membrane Proteins and Amyloid Fibrils.
Acc Chem Res. 2013 May 10;
Authors: Tang M, Comellas G, Rienstra CM
Abstract
Solid-state NMR (SSNMR) spectroscopy has become an important technique for studying the biophysics and structure biology of proteins. This technique is especially useful for insoluble membrane proteins and amyloid fibrils, which are essential for...
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05-11-2013 10:26 PM
Solid-state NMR analysis of interaction sites of curcumin and 42-residue amyloid ?-protein fibrils.
Solid-state NMR analysis of interaction sites of curcumin and 42-residue amyloid ?-protein fibrils.
Solid-state NMR analysis of interaction sites of curcumin and 42-residue amyloid ?-protein fibrils.
Bioorg Med Chem. 2011 Aug 27;
Authors: Masuda Y, Fukuchi M, Yatagawa T, Tada M, Takeda K, Irie K, Akagi KI, Monobe Y, Imazawa T, Takegoshi K
Abstract
Aggregation of 42-residue amyloid ?-protein (A?42) plays a pivotal role in the etiology of Alzheimer's disease (AD). Curcumin, the yellow pigment in the rhizome of turmeric, attracts...
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09-20-2011 03:10 PM
Structural Characterization of Polyglutamine Fibrils by Solid-State NMR Spectroscopy.
Structural Characterization of Polyglutamine Fibrils by Solid-State NMR Spectroscopy.
Structural Characterization of Polyglutamine Fibrils by Solid-State NMR Spectroscopy.
J Mol Biol. 2011 Jul 13;
Authors: Schneider R, Schumacher MC, Mueller H, Nand D, Klaukien V, Heise H, Riedel D, Wolf G, Behrmann E, Raunser S, Seidel R, Engelhard M, Baldus M
Protein aggregation via polyglutamine stretches occurs in a number of severe neurodegenerative diseases such as Huntington's disease. We have investigated fibrillar aggregates of polyglutamine peptides...
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07-19-2011 07:52 PM
The Core of Ure2p Prion Fibrils Is Formed by the N-Terminal Segment in a Parallel Cross-? Structure: Evidence from Solid-State NMR.
The Core of Ure2p Prion Fibrils Is Formed by the N-Terminal Segment in a Parallel Cross-? Structure: Evidence from Solid-State NMR.
The Core of Ure2p Prion Fibrils Is Formed by the N-Terminal Segment in a Parallel Cross-? Structure: Evidence from Solid-State NMR.
J Mol Biol. 2011 Apr 8;
Authors: Kryndushkin DS, Wickner RB, Tycko R
Intracellular fibril formation by Ure2p produces the non-Mendelian genetic element in Saccharomyces cerevisiae, making Ure2p a prion protein. We show that solid-state NMR spectra of full-length Ure2p fibrils, seeded...
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04-19-2011 11:01 PM
Atomic-resolution three-dimensional structure of HET-s(218-289) amyloid fibrils by solid-state NMR spectroscopy.
Atomic-resolution three-dimensional structure of HET-s(218-289) amyloid fibrils by solid-state NMR spectroscopy.
Atomic-resolution three-dimensional structure of HET-s(218-289) amyloid fibrils by solid-state NMR spectroscopy.
J Am Chem Soc. 2010 Oct 6;132(39):13765-75
Authors: Van Melckebeke H, Wasmer C, Lange A, Ab E, Loquet A, Böckmann A, Meier BH
We present a strategy to solve the high-resolution structure of amyloid fibrils by solid-state NMR and use it to determine the atomic-resolution structure of the prion domain of the fungal prion HET-s...
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01-21-2011 12:00 PM
Probing water-accessibility in HET-s(218-289) amyloid fibrils by solid-state NMR.
Probing water-accessibility in HET-s(218-289) amyloid fibrils by solid-state NMR.
Probing water-accessibility in HET-s(218-289) amyloid fibrils by solid-state NMR.
J Mol Biol. 2010 Nov 18;
Authors: Van Melckebeke H, Schanda P, Gath J, Wasmer C, Verel R, Lange A, Meier BH, Böckmann A
Despite its importance in the context of conformational diseases, structural information is still sparse for protein fibrils. Hydrogen/deuterium exchange measurements of backbone amides allow to identify hydrogen-bonding patterns and reveal pertinent information about...
Polyglutamine amyloid core boundaries and flanking domain dynamics in huntingtin fragment fibrils determined by solid-state NMR.
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