Flanking regions, amyloid cores, and polymorphism: the potential interplay underlying structural diversity

Bhopatkar, Anukool A.; Kayed, Rakez

doi:10.1016/j.jbc.2023.105122

Cited by 13 publications

(6 citation statements)

References 319 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the presence of residues undetectable in dipolar-based SSNMR experiments is not surprising, given that this observation has been made for most pathological and functional amyloids to date. 55,56 In light of these findings, we observed that the spectral resolution, as measured by the 13 C line width, is ~60-120 Hz (full width at half-height), which is indicative of a relatively well-ordered amyloid core. These observations are consistent with our previously reported 13 C line widths for B. subtilis TasA (~30-100 Hz), B. subtilis TapA (~200 Hz) and B. cereus CalY (~200 Hz), which, respectively form well-ordered amyloid fibrils (TasA) and polymorphic aggregates (TapA and CalY).…”

Section: N-domain 39-190 Displays the Canonical Cross-β Foldmentioning

confidence: 77%

See 1 more Smart Citation

CapP mediates the structural formation of biofilm-specific pili in the opportunistic human pathogenBacillus cereus

Álvarez-Mena,

Shukkoor,

Caro-Astorga

et al. 2024

Preprint

View full text Add to dashboard Cite

SUMMARYFibrillary proteins are structural scaffolds that diversify the functionality of the architectural bacterial extracellular matrix. Here, we report a previously uncharacterized bacterial factor calledbc1280that is exclusive toB. cereusgroup and indispensable for the establishment of a biofilm lifestyle. We propose that BC1280 is an architectural conductor for the assembly of the amyloid platform, leading to the polymerization of heteropili with two functional amyloids, CalY and TasA. From its cellular localization in the cell membrane, aggregates of BC1280 nucleate the polymerization of CalY, which further incorporates TasA into nascent pili. Additionally, BC1280 modulates the expression of EPS via an uncharacterized pathway that is activated by a protease and an ECF-type sigma factor. The pilus biogenesis system described in this work partially mirrors curli system inEscherichia coli, unveiling a new paradigm in the structural biology of gram-positive bacteria and highlighting the complexity of extracellular matrix assembly inB. cereus.

show abstract

Section: N-domain 39-190 Displays the Canonical Cross-β Foldmentioning

confidence: 77%

Section: Resultsmentioning

confidence: 99%

CapP mediates the structural formation of biofilm-specific pili in the opportunistic human pathogenBacillus cereus

Álvarez-Mena,

Shukkoor,

Caro-Astorga

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…This revealed the rigid polyQ core to be decorated with flexible, exposed, flanking domains ( Figure 1F,G ). This molecular architecture manifests in EM as a fuzzy coat, or a bottle-brush type architecture [ 71 ], a feature also seen in other pathogenic amyloid fibrils [ 74 , 75 ].…”

Section: Going Beyond the (Polyq) Core: Httex1 Flanking Domainsmentioning

confidence: 99%

Solid-state nuclear magnetic resonance in the structural study of polyglutamine aggregation

van der Wel

2024

Biochemical Society Transactions

View full text Add to dashboard Cite

The aggregation of proteins into amyloid-like fibrils is seen in many neurodegenerative diseases. Recent years have seen much progress in our understanding of these misfolded protein inclusions, thanks to advances in techniques such as solid-state nuclear magnetic resonance (ssNMR) spectroscopy and cryogenic electron microscopy (cryo-EM). However, multiple repeat-expansion-related disorders have presented special challenges to structural elucidation. This review discusses the special role of ssNMR analysis in the study of protein aggregates associated with CAG repeat expansion disorders. In these diseases, the misfolding and aggregation affect mutant proteins with expanded polyglutamine segments. The most common disorder, Huntington's disease (HD), is connected to the mutation of the huntingtin protein. Since the discovery of the genetic causes for HD in the 1990s, steady progress in our understanding of the role of protein aggregation has depended on the integrative and interdisciplinary use of multiple types of structural techniques. The heterogeneous and dynamic features of polyQ protein fibrils, and in particular those formed by huntingtin N-terminal fragments, have made these aggregates into challenging targets for structural analysis. ssNMR has offered unique insights into many aspects of these amyloid-like aggregates. These include the atomic-level structure of the polyglutamine core, but also measurements of dynamics and solvent accessibility of the non-core flanking domains of these fibrils' fuzzy coats. The obtained structural insights shed new light on pathogenic mechanisms behind this and other protein misfolding diseases.

show abstract

“…The structural models obtained from both filaments are missing about 20% of the Aβ42 sequence, represented by the N-terminal residues. This N-terminal regions is expected to remain disordered, displaying a high conformational heterogeneity, collectively forming a fuzzy coat around the cross-β core of the filaments (18-21). Further analysis of the structural properties of the disordered regions in the amyloid fibrils requires methods capable of characterizing conformational heterogeneity.…”

Section: Introductionmentioning

confidence: 99%

Transient interactions between the fuzzy coat and the cross-β core of brain-derived Aβ42 filaments

Milanesi,

Brotzakis,

Vendruscolo

2024

Preprint

View full text Add to dashboard Cite

A wide range of human disorders, including Alzheimer’s disease (AD), are characterised by the aberrant formation of amyloid fibrils. Amyloid fibrils are filamentous structures characterized by the presence of a highly-ordered cross-β core. In many cases, this core structure is flanked by disordered regions, often referred to as fuzzy coat. The structural properties of fuzzy coats, and the way in which they interact with their environments, however, have not been described in full detail to date. Here, we generated the conformational ensembles of two brain-derived amyloid filaments of Aβ42, corresponding respectively to familial and sporadic forms of AD. The approach that we used, called metadynamic electron microscopy metainference (MEMMI), enabled us to provide a characterization of the transient interactions between the fuzzy coat and the cross-β core of the filaments. These calculations indicated that the familial AD filaments are less soluble than the sporadic AD filaments, and that the fuzzy coat contributes to increasing the solubility of both types of filament. In addition, by analyzing the deviations between the density maps from cryo-EM and from the MEMMI structural ensembles, we observed a slowing down in the diffusion of water and sodium ions near the surface of the filaments, offering insight into the hydration dynamics of amyloid fibrils. These results illustrate how the metainference approach can help analyse cryo-EM maps for the characterisation of the properties of amyloid fibrils.

show abstract

Flanking regions, amyloid cores, and polymorphism: the potential interplay underlying structural diversity

Cited by 13 publications

References 319 publications

CapP mediates the structural formation of biofilm-specific pili in the opportunistic human pathogenBacillus cereus

CapP mediates the structural formation of biofilm-specific pili in the opportunistic human pathogenBacillus cereus

Solid-state nuclear magnetic resonance in the structural study of polyglutamine aggregation

Transient interactions between the fuzzy coat and the cross-β core of brain-derived Aβ42 filaments

Contact Info

Product

Resources

About