Amyloidogenicity at a Distance: How Distal Protein Regions Modulate Aggregation in Disease

Lucato, Christina M.; Lupton, Christopher J.; Halls, Michelle L.; Ellisdon, Andrew M.

doi:10.1016/j.jmb.2017.03.021

Cited by 8 publications

(9 citation statements)

References 155 publications

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“…The importance of flanking region(s) has been demonstrated for other aggregation-prone proteins, including the P17 region in exon 1 of huntingtin 25 , 26 , 28 , the N-terminal region (residue 11-16) of amyloid β (Aβ 40 ) 64 , residues 306-311 in tau 65 , the aggregation prone motifs 14–22, 53–58, and 69–72 in the N-terminal region of Apo-I 24 and the N-terminal six amino acids of β 2 -microglobulin 66 . At longer timescales, or under more favourable conditions for aggregation (e.g.…”

Section: Discussionmentioning

confidence: 99%

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A short motif in the N-terminal region of α-synuclein is critical for both aggregation and function

Doherty

Ulamec

Maya-Martinez

et al. 2020

Nat Struct Mol Biol

138

168

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Aggregation of human α-synuclein (αSyn) is linked to Parkinson’s disease (PD) pathology. The central region of the αSyn sequence contains the non-amyloid β-component (NAC) crucial for aggregation. However, how NAC flanking regions modulate αSyn aggregation remains unclear. Using bioinformatics, mutation, and NMR we identify a 7-residue sequence, named P1 (residues 36-42), that controls αSyn aggregation. Deletion or substitution of this ‘master-controller’ prevents aggregation at pH 7.5 in vitro. At lower pH, P1 synergises with a sequence containing the PreNAC region (P2, residues 45-57) to prevent aggregation. Deleting P1 (ΔP1) or both P1 and P2 (ΔΔ) also prevents age-dependent αSyn aggregation and toxicity in C. elegans models and prevents αSyn-mediated vesicle fusion by altering the conformational properties of the protein when lipid-bound. The results highlight the importance of a master-controller sequence motif that controls both αSyn aggregation and function- a region that could be targeted to prevent aggregation in disease.

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Section: Discussionmentioning

confidence: 99%

“…The effects of sequence changes on the conformational properties and aggregation rates of IDPs have been widely studied 24 – 28 . Notably for αSyn, the seven known familial point mutations that lead to early onset PD are clustered in a region (residues 30-53) that flanks NAC ( Figure 1A ).…”

Section: Introductionmentioning

confidence: 99%

A short motif in the N-terminal region of α-synuclein is critical for both aggregation and function

Doherty

Ulamec

Maya-Martinez

et al. 2020

Nat Struct Mol Biol

138

168

View full text Add to dashboard Cite

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“…The severity of a number of pathological conditions, such as Alzheimer's and Parkinson's disease, is associated with the deposition of amyloid plaques that contain mainly peptide or protein‐derived amyloid fibrils . The etiology of these conditions is proposed to involve the destruction of cellular membranes.…”

Section: Introductionmentioning

confidence: 99%

Amyloid aggregation and membrane activity of the antimicrobial peptide uperin 3.5

et al. 2018

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Amyloid fibrils are highly ordered, β‐sheet rich forms of aggregated peptides and proteins that are associated with a variety of pathological human disorders, including Alzheimer's and Parkinson's diseases. Amyloid fibril‐forming peptides may be functionally related to antimicrobial peptides, despite differing significantly in sequence and structure. Specifically, their interaction with lipid membranes has mechanistic similarities. The 17‐amino acid peptide uperin 3.5 (U3.5) from an Australian amphibian is antimicrobial and amyloidogenic. Using a quartz crystal microbalance, we investigated the interaction of U3.5 with artificial membranes and found that (i) the membrane interaction of U3.5 is independent of the peptide's aggregation state, (ii) the presence of cholesterol in the membrane dramatically alters peptide–membrane interaction leading to a transmembrane pore‐like arrangement of U3.5, and (iii) electrostatic interaction is important for the membrane activity of U3.5 whereby removal of the positive charge at position 7 of U3.5 enhanced its fibrillar aggregation and ablated its membrane interaction, i.e. there is an inverse relationship between the antimicrobial and amyloidogenic properties of U3.5.

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“…However, it has long been appreciated that distal portions of αS may play a role in aggregation, and that the N-terminus in particular may be more ordered than many structural methods have been capable of capturing. 9, 10, 19, 20…”

mentioning

confidence: 99%

Fluorescence spectroscopy reveals N-terminal order in fibrillar forms of α-synuclein

Haney

Petersson

2018

Chem. Commun.

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The neuronal protein α-synuclein (αS) plays a key role in Parkinson's disease, forming inclusions termed Lewy bodies and Lewy neurites. Recent improvements in cryo-electron diffraction and solid state NMR (ssNMR) have led to the elucidation of the structures of peptides derived from the αS fibril core and full-length human αS in fibrils. Despite the valuable insight offered by these methods, there are still several questions about the structures' relevance to pathological aggregates. Herein, we present fluorescence data collected in vitro under the conditions which fibrils are typically assembled. Our data suggest that, in solution, fibrils are largely structured as observed by ssNMR. However, we observe significant disparities in the αS N-terminus as compared to ssNMR data, which provide insight on its important role in αS aggregation and fibril structure.

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Amyloidogenicity at a Distance: How Distal Protein Regions Modulate Aggregation in Disease

Cited by 8 publications

References 155 publications

A short motif in the N-terminal region of α-synuclein is critical for both aggregation and function

A short motif in the N-terminal region of α-synuclein is critical for both aggregation and function

Amyloid aggregation and membrane activity of the antimicrobial peptide uperin 3.5

Fluorescence spectroscopy reveals N-terminal order in fibrillar forms of α-synuclein

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