Therapeutic approaches against common structural features of toxic oligomers shared by multiple amyloidogenic proteins

2014 ◽  
Vol 88 (4) ◽  
pp. 468-478 ◽  
Author(s):  
Marcos J. Guerrero-Muñoz ◽  
Diana L. Castillo-Carranza ◽  
Rakez Kayed
Keyword(s):  
Structural Features ◽  
Therapeutic Approaches ◽  
Amyloidogenic Proteins

scholarly journals Computational molecular modelling as a platform for a deeper understanding of protein dynamics and rational drug design

2020 ◽  
Author(s):  
Gianvito Grasso ◽  
Lorenzo Pallante ◽  
Jack A. Tuszynski ◽  
Umberto Morbiducci ◽  
Marco A. Deriu
Keyword(s):  
Molecular Modelling ◽  
Molecular Level ◽  
Structural Features ◽  
Rational Drug Design ◽  
Therapeutic Approaches ◽  
Amyloidogenic Proteins ◽  
Rational Drug ◽  
Aggregation Inhibitors ◽  
The Stability ◽  
Toxicity Pathways

Elucidating structural features of protein aggregation at molecular level may provide novel opportunities for overarching therapeutic approaches such as blocking common aggregation-induced cellular toxicity pathways. In this context molecular modelling stimulates further research on amyloid aggregation modulators and modelling platforms can be used to test the efficiency of potential aggregation inhibitors aimed at destabilizing/reducing the stability of the amyloidogenic proteins

scholarly journals Atg8-Family Proteins—Structural Features and Molecular Interactions in Autophagy and Beyond

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2008 ◽  
Author(s):  
Nicole Wesch ◽  
Vladimir Kirkin ◽  
Vladimir V. Rogov
Keyword(s):  
Protein Interactions ◽  
Membrane Trafficking ◽  
Structural Features ◽  
Structural Level ◽  
Interacting Proteins ◽  
Therapeutic Approaches ◽  
Basic Principles ◽  
Interaction Partners ◽  
Shed Light

Autophagy is a common name for a number of catabolic processes, which keep the cellular homeostasis by removing damaged and dysfunctional intracellular components. Impairment or misbalance of autophagy can lead to various diseases, such as neurodegeneration, infection diseases, and cancer. A central axis of autophagy is formed along the interactions of autophagy modifiers (Atg8-family proteins) with a variety of their cellular counter partners. Besides autophagy, Atg8-proteins participate in many other pathways, among which membrane trafficking and neuronal signaling are the most known. Despite the fact that autophagy modifiers are well-studied, as the small globular proteins show similarity to ubiquitin on a structural level, the mechanism of their interactions are still not completely understood. A thorough analysis and classification of all known mechanisms of Atg8-protein interactions could shed light on their functioning and connect the pathways involving Atg8-proteins. In this review, we present our views of the key features of the Atg8-proteins and describe the basic principles of their recognition and binding by interaction partners. We discuss affinity and selectivity of their interactions as well as provide perspectives for discovery of new Atg8-interacting proteins and therapeutic approaches to tackle major human diseases.

scholarly journals High-speed atomic force microscopy reveals structural dynamics of amyloid β1–42 aggregates

2016 ◽  
Vol 113 (21) ◽  
pp. 5835-5840 ◽  
Author(s):  
Takahiro Watanabe-Nakayama ◽  
Kenjiro Ono ◽  
Masahiro Itami ◽  
Ryoichi Takahashi ◽  
David B. Teplow ◽  
...  
Keyword(s):  
Atomic Force Microscopy ◽  
High Speed ◽  
Amyloid Β ◽  
Structural Features ◽  
Molecular Structures ◽  
Amyloid Β Protein ◽  
Force Microscopy ◽  
Amyloidogenic Proteins ◽  
Atomic Force ◽  
Growth Modes

Aggregation of amyloidogenic proteins into insoluble amyloid fibrils is implicated in various neurodegenerative diseases. This process involves protein assembly into oligomeric intermediates and fibrils with highly polymorphic molecular structures. These structural differences may be responsible for different disease presentations. For this reason, elucidation of the structural features and assembly kinetics of amyloidogenic proteins has been an area of intense study. We report here the results of high-speed atomic force microscopy (HS-AFM) studies of fibril formation and elongation by the 42-residue form of the amyloid β-protein (Aβ1–42), a key pathogenetic agent of Alzheimer's disease. Our data demonstrate two different growth modes of Aβ1–42, one producing straight fibrils and the other producing spiral fibrils. Each mode depends on initial fibril nucleus structure, but switching from one growth mode to another was occasionally observed, suggesting that fibril end structure fluctuated between the two growth modes. This switching phenomenon was affected by buffer salt composition. Our findings indicate that polymorphism in fibril structure can occur after fibril nucleation and is affected by relatively modest changes in environmental conditions.

scholarly journals Pseudokinases: From Allosteric Regulation of Catalytic Domains and the Formation of Macromolecular Assemblies to Emerging Drug Targets

Catalysts ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 778 ◽  
Author(s):  
Andrada Tomoni ◽  
Jonathan Lees ◽  
Andrés G. Santana ◽  
Victor M. Bolanos-Garcia ◽  
Agatha Bastida
Keyword(s):  
Cell Proliferation ◽  
Protein Interactions ◽  
Drug Targets ◽  
Structural Features ◽  
Therapeutic Window ◽  
Amino Acid Residues ◽  
Protein Protein Interactions ◽  
Therapeutic Approaches ◽  
Macromolecular Assemblies ◽  
Catalytic Domains

Pseudokinases are a member of the kinase superfamily that lack one or more of the canonical residues required for catalysis. Protein pseudokinases are widely distributed across species and are present in proteins that perform a great diversity of roles in the cell. They represent approximately 10% to 40% of the kinome of a multicellular organism. In the human, the pseudokinase subfamily consists of approximately 60 unique proteins. Despite their lack of one or more of the amino acid residues typically required for the productive interaction with ATP and metal ions, which is essential for the phosphorylation of specific substrates, pseudokinases are important functional molecules that can act as dynamic scaffolds, competitors, or modulators of protein–protein interactions. Indeed, pseudokinase misfunctions occur in diverse diseases and represent a new therapeutic window for the development of innovative therapeutic approaches. In this contribution, we describe the structural features of pseudokinases that are used as the basis of their classification; analyse the interactome space of human pseudokinases and discuss their potential as suitable drug targets for the treatment of various diseases, including metabolic, neurological, autoimmune, and cell proliferation disorders.

Electron microscopy and diffraction studies of polyimides

1983 ◽  
Vol 41 ◽  
pp. 28-29
Author(s):  
O.C. de Hodgins ◽  
K. R. Lawless ◽  
R. Anderson
Keyword(s):  
Electron Microscopy ◽  
Electron Microscope ◽  
Structural Features ◽  
Inert Atmosphere ◽  
Polyimide Films ◽  
Resolution Electron ◽  
The Matrix ◽  
High Resolution Electron Microscope ◽  
Diffraction Patterns ◽  
Polymeric Samples

Commercial polyimide films have shown to be homogeneous on a scale of 5 to 200 nm. The observation of Skybond (SKB) 705 and PI5878 was carried out by using a Philips 400, 120 KeV STEM. The objective was to elucidate the structural features of the polymeric samples. The specimens were spun and cured at stepped temperatures in an inert atmosphere and cooled slowly for eight hours. TEM micrographs showed heterogeneities (or nodular structures) generally on a scale of 100 nm for PI5878 and approximately 40 nm for SKB 705, present in large volume fractions of both specimens. See Figures 1 and 2. It is possible that the nodulus observed may be associated with surface effects and the structure of the polymers be regarded as random amorphous arrays. Diffraction patterns of the matrix and the nodular areas showed different amorphous ring patterns in both materials. The specimens were viewed in both bright and dark fields using a high resolution electron microscope which provided magnifications of 100,000X or more on the photographic plates if desired.

Skeletal elements of crinoid echinoderms: High-resolution structural and microanalytical results

1983 ◽  
Vol 41 ◽  
pp. 194-195
Author(s):  
D. F. Blake ◽  
L. F. Allard ◽  
D. R. Peacor
Keyword(s):  
High Resolution ◽  
Marine Invertebrates ◽  
Sea Urchins ◽  
Structural Features ◽  
Sea Stars ◽  
High Resolution Tem ◽  
Relationship Of ◽  
The Relationship ◽  
Insight Into

Echinodermata is a phylum of marine invertebrates which has been extant since Cambrian time (c.a. 500 m.y. before the present). Modern examples of echinoderms include sea urchins, sea stars, and sea lilies (crinoids). The endoskeletons of echinoderms are composed of plates or ossicles (Fig. 1) which are with few exceptions, porous, single crystals of high-magnesian calcite. Despite their single crystal nature, fracture surfaces do not exhibit the near-perfect {10.4} cleavage characteristic of inorganic calcite. This paradoxical mix of biogenic and inorganic features has prompted much recent work on echinoderm skeletal crystallography. Furthermore, fossil echinoderm hard parts comprise a volumetrically significant portion of some marine limestones sequences. The ultrastructural and microchemical characterization of modern skeletal material should lend insight into: 1). The nature of the biogenic processes involved, for example, the relationship of Mg heterogeneity to morphological and structural features in modern echinoderm material, and 2). The nature of the diagenetic changes undergone by their ancient, fossilized counterparts. In this study, high resolution TEM (HRTEM), high voltage TEM (HVTEM), and STEM microanalysis are used to characterize tha ultrastructural and microchemical composition of skeletal elements of the modern crinoid Neocrinus blakei.

Study of the Molecular Architecture of Keratin Filaments by Electron Microscopy

1982 ◽  
Vol 40 ◽  
pp. 118-119
Author(s):  
U. Aebi ◽  
P. Rew ◽  
T.-T. Sun
Keyword(s):  
Electron Microscopy ◽  
Structural Organization ◽  
Cell Types ◽  
Structural Features ◽  
Molecular Architecture ◽  
The Past ◽  
Keratin Filaments ◽  
Different Types ◽  
10 Nm Filaments ◽  
Different Cell Types

Various types of intermediate-sized (10-nm) filaments have been found and described in many different cell types during the past few years. Despite the differences in the chemical composition among the different types of filaments, they all yield common structural features: they are usually up to several microns long and have a diameter of 7 to 10 nm; there is evidence that they are made of several 2 to 3.5 nm wide protofilaments which are helically wound around each other; the secondary structure of the polypeptides constituting the filaments is rich in ∞-helix. However a detailed description of their structural organization is lacking to date.

Measurement and Reduction of Radiation Damage in Frozen Hydrated Crystalline Specimens

1978 ◽  
Vol 36 (3) ◽  
pp. 70-77 ◽  
Author(s):  
R.M. Glaeser ◽  
S.B. Hayward
Keyword(s):  
Diffraction Pattern ◽  
Structural Information ◽  
Structural Disorder ◽  
Structural Features ◽  
Biological Macromolecules ◽  
Diffraction Intensity ◽  
Object Structure ◽  
Specimen Material ◽  
Unit Cells ◽  
Identical Unit

Highly ordered or crystalline biological macromolecules become severely damaged and structurally disordered after a brief electron exposure. Evidence that damage and structural disorder are occurring is clearly given by the fading and eventual disappearance of the specimen's electron diffraction pattern. The fading and disappearance of sharp diffraction spots implies a corresponding disappearance of periodic structural features in the specimen. By the same token, there is a oneto- one correspondence between the disappearance of the crystalline diffraction pattern and the disappearance of reproducible structural information that can be observed in the images of identical unit cells of the object structure. The electron exposures that result in a significant decrease in the diffraction intensity will depend somewhat upon the resolution (Bragg spacing) involved, and can vary considerably with the chemical makeup and composition of the specimen material.

Some Structural Features of Metaphase Chromosomes of Mice and Men

1967 ◽  
Vol 25 ◽  
pp. 190-191
Author(s):  
Godfrey C. Hoskins ◽  
Betty B. Hoskins
Keyword(s):  
Electron Microscopy ◽  
Electron Micrographs ◽  
Structural Features ◽  
Metaphase Chromosomes ◽  
The Future ◽  
Of Mice And Men ◽  
Mouse Cells ◽  
Human And Mouse

Metaphase chromosomes from human and mouse cells in vitro are isolated by micrurgy, fixed, and placed on grids for electron microscopy. Interpretations of electron micrographs by current methods indicate the following structural features.Chromosomal spindle fibrils about 200Å thick form fascicles about 600Å thick, wrapped by dense spiraling fibrils (DSF) less than 100Å thick as they near the kinomere. Such a fascicle joins the future daughter kinomere of each metaphase chromatid with those of adjacent non-homologous chromatids to either side. Thus, four fascicles (SF, 1-4) attach to each metaphase kinomere (K). It is thought that fascicles extend from the kinomere poleward, fray out to let chromosomal fibrils act as traction fibrils against polar fibrils, then regroup to join the adjacent kinomere.

Sign in / Sign up

Export Citation Format

Share Document