Functional amyloids from bacterial biofilms – structural properties and interaction partners

Chemical Science, Год журнала: 2022, Номер 13(22), С. 6457 - 6477

Опубликована: Янв. 1, 2022

Functional bacterial amyloids forming biofilms have unique structural characteristics while still being similar to pathological ones. Through many identified interaction partners, they emerge as complex and essential components of biofilms.

Язык: Английский

---

General Principles Underpinning Amyloid Structure

Frontiers in Neuroscience, Год журнала: 2022, Номер 16

Опубликована: Июнь 2, 2022

Amyloid fibrils are a pathologically and functionally relevant state of protein folding, which is generally accessible to polypeptide chains differs fundamentally from the globular in terms molecular symmetry, long-range conformational order, supramolecular scale. Although amyloid structures challenging study, recent developments techniques such as cryo-EM, solid-state NMR, AFM have led an explosion information about organization these assemblies. With rapid advances, it now possible assess prevalence significance proposed general structural features context diverse body high-resolution models, develop unified view principles that control formation give rise their unique properties. Here, we show that, despite system-specific differences, there remarkable degree commonality both motifs amyloids adopt underlying responsible for them. We argue inherent geometric differences between proteins shift balance stabilizing forces, predisposing distinct interaction with particular tendency massive, lattice-like networks mutually supporting interactions. This property unites previously characterized steric polar zippers, contributes order gives many The shared support existence structure-activity explain self-assembly, function, pathogenesis, instill hope efforts broad-spectrum modifiers function pathology.

Язык: Английский

---

Learning and memory using Drosophila melanogaster: a focus on advances made in the fifth decade of research

Genetics, Год журнала: 2023, Номер 224(4)

Опубликована: Май 22, 2023

Abstract In the last decade, researchers using Drosophila melanogaster have made extraordinary progress in uncovering mysteries underlying learning and memory. This has been propelled by amazing toolkit available that affords combined behavioral, molecular, electrophysiological, systems neuroscience approaches. The arduous reconstruction of electron microscopic images resulted a first-generation connectome adult larval brain, revealing complex structural interconnections between memory-related neurons. serves as substrate for future investigations on these connections building complete circuits from sensory cue detection to changes motor behavior. Mushroom body output neurons (MBOn) were discovered, which individually forward information discrete non-overlapping compartments axons mushroom (MBn). These mirror previously discovered tiling inputs dopamine led model ascribes valence event, either appetitive or aversive, activity different populations balance MBOn promoting avoidance approach Studies calyx, houses MBn dendrites, revealed beautiful microglomeruluar organization synapses occur with long-term memory (LTM) formation. Larval advanced, positioning it possibly lead producing new conceptual insights due its markedly simpler structure over brain. Advances how cAMP response element-binding protein interacts kinases other transcription factors promote formation LTM. New Orb2, prion-like forms oligomers enhance synaptic synthesis required LTM Finally, research pioneered our understanding mechanisms mediate permanent transient active forgetting, an important function brain along acquisition, consolidation, retrieval. was catalyzed partly identification suppressor genes—genes whose normal is limit

Язык: Английский

---

Structural analysis and architectural principles of the bacterial amyloid curli

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Май 17, 2023

Abstract Two decades have passed since the initial proposition that amyloids are not only (toxic) byproducts of an unintended aggregation cascade, but they can also be produced by organism to serve a defined biological function. That revolutionary idea was borne out realization large fraction extracellular matrix holds Gram-negative cells into persistent biofilm is composed protein fibers (curli; tafi) with cross-β architecture, nucleation-dependent polymerization kinetics and classic amyloid tinctorial properties. The list proteins shown form so-called functional in vivo has greatly expanded over years, detailed structural insights followed at similar pace part due associated experimental barriers. Here we combine extensive AlphaFold2 modelling cryo-electron transmission microscopy propose atomic model curli protofibrils, their higher modes organization. We uncover unexpected diversity building blocks fibril architectures. Our results allow for rationalization extreme physico-chemical robustness curli, as well earlier observations inter-species promiscuity, should facilitate further engineering efforts expand repertoire curli-based materials.

Язык: Английский

---

Development of Small Molecules Targeting α-Synuclein Aggregation: A Promising Strategy to Treat Parkinson’s Disease

Pharmaceutics, Год журнала: 2023, Номер 15(3), С. 839 - 839

Опубликована: Март 3, 2023

Parkinson’s disease, the second most common neurodegenerative disorder worldwide, is characterized by accumulation of protein deposits in dopaminergic neurons. These are primarily composed aggregated forms α-Synuclein (α-Syn). Despite extensive research on this only symptomatic treatments currently available. However, recent years, several compounds, mainly an aromatic character, targeting α-Syn self-assembly and amyloid formation have been identified. discovered different approaches, chemically diverse exhibit a plethora mechanisms action. This work aims to provide historical overview physiopathology molecular aspects associated with disease current trends small compound development target aggregation. Although these molecules still under development, they constitute important step toward discovering effective anti-aggregational therapies for disease.

Язык: Английский

---

Functional Amyloids: Where Supramolecular Amyloid Assembly Controls Biological Activity or Generates New Functionality

Journal of Molecular Biology, Год журнала: 2023, Номер 435(11), С. 167919 - 167919

Опубликована: Июнь 1, 2023

Язык: Английский

---

Identification of protein aggregates in the aging vertebrate brain with prion-like and phase-separation properties

Cell Reports, Год журнала: 2024, Номер 43(6), С. 112787 - 112787

Опубликована: Май 28, 2024

Protein aggregation, which can sometimes spread in a prion-like manner, is hallmark of neurodegenerative diseases. However, whether aggregates form during normal brain aging remains unknown. Here, we use quantitative proteomics the African turquoise killifish to identify protein that accumulate old vertebrate brains. These are enriched for RNA-binding proteins, notably ATP-dependent RNA helicase DDX5. We validate DDX5 forms aggregate-like puncta brains and mice. Interestingly, DDX5's domain allows these propagate across many generations yeast. In vitro, phase separates into condensates. Mutations abolish prion propagation also impair protein's ability separate. condensates exhibit enhanced enzymatic activity, but they mature inactive, solid aggregates. Our findings suggest with properties aging, could have implications age-dependency cognitive decline.

Язык: Английский

---

The role of disorder in RNA binding affinity and specificity

Open Biology, Год журнала: 2020, Номер 10(12)

Опубликована: Дек. 1, 2020

Most RNA-binding modules are small and bind few nucleotides. proteins typically attain the physiological specificity affinity for their RNA targets by combining several modules. Here, we review how disordered linkers connecting govern of RNA–protein interactions regulating effective concentration these relative orientation. also often contain extended intrinsically regions that mediate protein–protein with multiple partners. We discuss can connect resulting in heterogeneous higher-order assemblies such as membrane-less compartments amyloid-like structures have characteristics multi-modular entities. The assembled state generates additional properties contribute to further function within cellular environment.

Язык: Английский

---

pH-Responsive Self-Assembly of Amyloid Fibrils for Dual Hydrolase-Oxidase Reactions

ACS Catalysis, Год журнала: 2020, Номер 11(2), С. 595 - 607

Опубликована: Дек. 29, 2020

There is an increasing interest in synthetic systems that can execute bioinspired chemical reactions without requiring the complex structures characterize enzymes their components. The hierarchical self-assembly of peptides provides a means to create catalytic microenvironments. Ideally, as it occurs enzymes, activity peptide nanostructures should be reversibly regulated. In typical enzyme mimetic design, peptide's self-assembling and activities are segregated into different regions sequence. Here, we aimed design minimal which function were all encoded same amino acids. Moreover, wanted endow resulting one-component nanomaterial with divergent, chemically unrelated, activities, property not observed natural enzymes. We show short consisting only histidine tyrosine residues, arranged binary pattern, form biocompatible amyloid-like fibrils hydrogels combining hydrolytic electrocatalytic activities. nanofibers' mesoscopic properties controlled by pH, transition between assembled active β-sheet fibrils, disassembled inactive random coil species occurring physiologically relevant pH range. structure one such derived from molecular dynamic simulations, insights on how they attain this combination structural properties.

Язык: Английский

---

Integrative Structural Biology in the Era of Accurate Structure Prediction

Journal of Molecular Biology, Год журнала: 2021, Номер 433(20), С. 167127 - 167127

Опубликована: Июль 3, 2021

Characterizing the three-dimensional structure of macromolecules is central to understanding their function. Traditionally, structures proteins and complexes have been determined using experimental techniques such as X-ray crystallography, NMR, or cryo-electron microscopy-applied individually in an integrative manner. Meanwhile, however, computational methods for protein prediction improving accuracy, gradually, then suddenly, with breakthrough advance by AlphaFold2, whose models monomeric are often accurate structures. This foreshadows a new era that can build most proteins. Here, we envision how modeling combine structural biology techniques, enhancing biology. We highlight challenges arise when considering multiple conformations, complexes, polymorphic assemblies. These will motivate further developments, both programs solve structures, towards better quicker investigation structure-function relationships.

Язык: Английский

---