Post-aggregation Oxidation of Mutant Huntingtin Controls the Interactions between Aggregates

Mitomi, Yasushi; Nomura, Takao; Kurosawa, Masaru; Nukina, Nobuyuki; Furukawa, Yoshiaki

doi:10.1074/jbc.m112.387035

Cited by 29 publications

(33 citation statements)

References 51 publications

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“…Oxidized hIAPP stabilizes an α-helical structure at the N-terminus, protecting the peptide from amyloid formation and safeguarding its activity in insulin and glucagon secretion as well as reducing food intake and gastric emptying [103,104]. A similar mechanism has been published for β-microglobulin and endostatin, for which two disulfide bonds guard its native folded conformation [105][106][107].…”

Section: Cysteine Oxidation-driven Protein Aggregation In Diseasementioning

confidence: 74%

“…Furthermore, oxidation does not only trigger aggregation. Post-aggregation oxidation of proteins seems to be widespread, changing the structural conformation of established aggregates of proteins including huntingtin and β-microglobulin [106,107]. Besides providing an explanation for the abundance of oxidative modifications found in aggregate deposits, this finding suggests that insoluble aggregates are not inert protein disposals but can still alter their structure and interactions due to redox-dependent post-aggregation modifications.…”

Section: Cysteine Oxidation-driven Protein Aggregation In Diseasementioning

confidence: 92%

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Cross-talk between redox signalling and protein aggregation

Dam

Dansen

2020

Biochemical Society Transactions

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It is well established that both an increase in reactive oxygen species (ROS: i.e. O2•−, H2O2 and OH•), as well as protein aggregation, accompany ageing and proteinopathies such as Parkinson's and Alzheimer's disease. However, it is far from clear whether there is a causal relation between the two. This review describes how protein aggregation can be affected both by redox signalling (downstream of H2O2), as well as by ROS-induced damage, and aims to give an overview of the current knowledge of how redox signalling affects protein aggregation and vice versa. Redox signalling has been shown to play roles in almost every step of protein aggregation and amyloid formation, from aggregation initiation to the rapid oligomerization of large amyloids, which tend to be less toxic than oligomeric prefibrillar aggregates. We explore the hypothesis that age-associated elevated ROS production could be part of a redox signalling-dependent-stress response in an attempt to curb protein aggregation and minimize toxicity.

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Section: Cysteine Oxidation-driven Protein Aggregation In Diseasementioning

confidence: 74%

Section: Cysteine Oxidation-driven Protein Aggregation In Diseasementioning

confidence: 92%

Cross-talk between redox signalling and protein aggregation

Dam

Dansen

2020

Biochemical Society Transactions

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“…Multiple PTM’s have been implicated in accelerating or inhibiting huntingtin exon 1 aggregation (14–16, 78, 79), while some have been implicated in promoting new morphologies from pre-aggregated species (80). Phosphorylation of Thr3 leads to decreased toxicity but increased aggregation rates (16).…”

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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“…Here, we show that NOR3-induced GAPDH aggregation is a useful example of how oxidation of a surface-exposed "linchpin" residue can drive protein misfolding and aggregation. A similar sequence of events has been proposed for the aggregation of numerous other proteins that are structurally unrelated to GAPDH, including human growth hormone (49), transthyretin (50), Fas ligand (51), apolipoprotein A-I (52), interferon ␤1a (53), huntingtin (54), -casein (55), and ␥-synuclein (56). Indeed, as free radicalinduced protein misfolding is a widely accepted factor in aging and neurodegenerative disease (40), we anticipate that our novel tripartite ranking method can be used to expedite the identification of linchpin residues in other important free radical-induced protein aggregation events.…”

Section: Discussionmentioning

confidence: 99%

Oxidation of an Exposed Methionine Instigates the Aggregation of Glyceraldehyde-3-phosphate Dehydrogenase

Samson

Knaupp

Kass

et al. 2014

Journal of Biological Chemistry

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Background: GAPDH is a glycolytic enzyme that aggregates during disease. Cysteine oxidation is the putative cause of aggregation. Whether GAPDH aggregation influences disease is unknown. Results: Mutating Met-46 renders GAPDH resistant to free radical-induced aggregation. Conclusion: Methionine oxidation, rather than cysteine oxidation, is a primary event that instigates GAPDH aggregation. Significance: Mutating Met-46 in vivo should elucidate whether GAPDH aggregation causally contributes to disease.

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Post-aggregation Oxidation of Mutant Huntingtin Controls the Interactions between Aggregates

Cited by 29 publications

References 51 publications

Cross-talk between redox signalling and protein aggregation

Cross-talk between redox signalling and protein aggregation

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

Oxidation of an Exposed Methionine Instigates the Aggregation of Glyceraldehyde-3-phosphate Dehydrogenase

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