The Effects of Flanking Sequences in the Interaction of Polyglutamine Peptides with a Membrane Bilayer

Nagarajan, Anu; Jawahery, Sudi; Matysiak, Silvina

doi:10.1021/jp407900c

Cited by 26 publications

(53 citation statements)

References 62 publications

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“…However, both Nt17 and a C-terminal polyP domain were required for polyQ peptides to destabilize membrane structure, leading to leakage. Computational studies further support the important role of Nt17 in htt/lipid interactions and also provide evidence that the presence of both Nt17 and polyP enhance the interaction of htt with bilayers (84). The cooperative effect of Nt17 and the polyP domain in disrupting membranes may be particularly important in light of observed interactions between these two domains in a cellular environment that is altered with increasing polyQ length (145).…”

Section: Nt17 Mediates Htt/lipid Interactions With Potential Implicatmentioning

confidence: 66%

“…It would appear that residues in the boundary region are critical in lipid membrane binding and intermolecular interaction. Simulation of lipid membrane association show K6 and K15 are strong hydrogen bond donors with lipid bilayers (84). Similarly, K6 was found to be protected in an aggregated state by solution phase deuterium exchange mass spectrometry (85).…”

Section: Nt17 Structure In Monomeric and Aggregated Httmentioning

confidence: 99%

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The emerging role of the first 17 amino acids of huntingtin in Huntington’s disease

Arndt

Chaibva

Legleiter³

2015

Biomolecular Concepts

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Huntington’s disease (HD) is caused by a polyglutamine (polyQ) domain that is expanded beyond a critical threshold near the N-terminus of the huningtin (htt) protein, directly leading to htt aggregation. While full-length htt is a large (on the order of ~350 kDa) protein, it is proteolyzed into a variety of N-terminal fragments that accumulate in oligomers, fibrils, and larger aggregates. It is clear that polyQ length is a key determinant of htt aggregation and toxicity. However, the flanking sequences around polyQ domain, such as the first seventeen amino acids on the N terminus (Nt17), influence aggregation, aggregate stability, other important biochemical properties of the protein, and ultimately it role in pathogenesis. Here, we review the impact of Nt17 on both htt aggregation mechanisms and kinetics, structural properties of Nt17 in both monomeric and aggregate forms, the potential role of post translational modifications (PTMs) that occur in Nt17 in HD, and Nt17’s function as a membrane targeting domain.

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Section: Nt17 Mediates Htt/lipid Interactions With Potential Implicatmentioning

confidence: 66%

Section: Nt17 Structure In Monomeric and Aggregated Httmentioning

confidence: 99%

The emerging role of the first 17 amino acids of huntingtin in Huntington’s disease

Arndt

Chaibva

Legleiter³

2015

Biomolecular Concepts

View full text Add to dashboard Cite

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“…Additionally, simulations of gas-phase dimer interactions show the involvement of Lys6 in stabilizing hydrogen bond interactions with oxygen-containing residues. Multiple solution simulations show that Lys6 is contained in the helical portion of Nt17, whether in its monomeric form (17) or bound to a lipid substrate (6, 7, 82). While the current study did not probe aggregation kinetics, the study does suggest that modifying the ε-amino group on Lys6 inhibits inter-helical association.…”

Section: Resultsmentioning

confidence: 99%

Huntingtin N-Terminal Monomeric and Multimeric Structures Destabilized by Covalent Modification of Heteroatomic Residues

et al. 2015

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Early-stage oligomer formation of the huntingtin protein may be driven by self-association of the seventeen-residue amphipathic α-helix at the protein’s N-terminus (Nt17). Oligomeric structures have been implicated in neuronal toxicity and may represent important neurotoxic species in Huntington’s disease. Therefore, a residue-specific structural characterization of Nt17 is crucial to understanding and potentially inhibiting oligomer formation. Native electrospray ion mobility spectrometry-mass spectrometry (IMS-MS) techniques and molecular dynamics simulations (MDS), have been applied to study coexisting monomer and multimer conformations of Nt17, independent of the remainder of huntingtin exon 1. MDS suggests gas-phase monomer ion structures are comprised of a helix-turn-coil configuration and a helix-extended coil region. Elongated dimer species are comprised of partially-helical monomers arranged in an antiparallel geometry. This stacked helical bundle may represent the earliest stages of Nt17-driven oligomer formation. Nt17 monomers and multimers have been further probed using diethylpyrocarbonate (DEPC). An N-terminal site (N-terminus of Threonine-3) and Lysine-6 are modified at higher DEPC concentrations, which led to the formation of an intermediate monomer structure. These modifications resulted in decreased extended monomer ion conformers, as well as a reduction in multimer formation. From the MDS experiments for the dimer ions, Lys6 residues in both monomer constituents interact with Ser16 and Glu12 residues on adjacent peptides; therefore, the decrease in multimer formation could result from disruption of these or similar interactions. This work provides a structurally selective model from which to study Nt17 self-association and provides critical insight toward Nt17 multimerization and possibly, the early stages of huntingtin exon 1 aggregation.

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“…179 This observation was further supported by computational studies demonstrating that N17 regulates htt/lipid interactions and the presence of both N17 and polyP enhance the interaction of htt with bilayers. 211 …”

Section: Flanking Sequences Adjacent To Polyq Tracts Influence Aggregmentioning

confidence: 99%

Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease

et al. 2017

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Several hereditary neurological and neuromuscular diseases are caused by an abnormal expansion of trinucleotide repeats. To date, there have been ten of these trinucleotide repeat disorders associated with an expansion of the codon CAG encoding glutamine (Q). For these polyglutamine (polyQ) diseases, there is a critical threshold length of the CAG repeat required for disease, and further expansion beyond this threshold is correlated with age of onset and symptom severity. PolyQ expansion in the translated proteins promotes their self-assembly into a variety of oligomeric and fibrillar aggregate species that accumulate into the hallmark proteinaceous inclusion bodies associated with each disease. Here, we review aggregation mechanisms of proteins with expanded polyQ-tracts, structural consequences of expanded polyQ ranging from monomers to fibrillar aggregates, the impact of protein context and post translational modifications on aggregation, and a potential role for lipids membranes in aggregation. As the pathogenic mechanisms that underlie these disorders are often classified as either a gain of toxic function or loss of normal protein function, some toxic mechanisms associated with mutant polyQ tracts will also be discussed.

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The Effects of Flanking Sequences in the Interaction of Polyglutamine Peptides with a Membrane Bilayer

Cited by 26 publications

References 62 publications

The emerging role of the first 17 amino acids of huntingtin in Huntington’s disease

The emerging role of the first 17 amino acids of huntingtin in Huntington’s disease

Huntingtin N-Terminal Monomeric and Multimeric Structures Destabilized by Covalent Modification of Heteroatomic Residues

Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease

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