scholarly journals Structural mechanism for bi-directional actin crosslinking by T-plastin

2021 ◽  
Author(s):  
Lin Mei ◽  
Matthew J Reynolds ◽  
Damien Garbett ◽  
Rui Gong ◽  
Tobias Meyer ◽  
...  
Keyword(s):  
Bone Diseases ◽  
Biological Data ◽  
Structural Elements ◽  
Structural Mechanism ◽  
Actin Networks ◽  
Network Geometry ◽  
Cytoskeletal Network ◽  
Mixed Polarity ◽  
Scale Network ◽  
Structural Mechanisms

To fulfill the cytoskeleton's diverse functions in cell mechanics and motility, actin networks with specialized architectures are built by crosslinking proteins, which bridge filaments to control micron-scale network geometry through nanoscale binding interactions via poorly defined structural mechanisms. Here, we introduce a machine-learning enabled cryo-EM pipeline for visualizing active crosslinkers, which we use to analyze human T-plastin, a member of the evolutionarily ancient plastin/fimbrin family of tandem calponin-homology domain (CHD) proteins. We define a sequential bundling mechanism which enables T-plastin to bridge filaments in both parallel and anti-parallel orientations. Our structural, biochemical, and cell biological data highlight inter-CHD linkers as key structural elements underlying flexible but stable crosslinking which are likely to be disrupted by mutations causing hereditary bone diseases. Beyond revealing how plastins are evolutionary optimized to crosslink dense actin networks with mixed polarity, our cryo-EM workflow will broadly enable analysis of the structural mechanisms underlying cytoskeletal network construction.

scholarly journals The dynamics of faculty hiring networks

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Eun Lee ◽  
Aaron Clauset ◽  
Daniel B. Larremore
Keyword(s):  
Network Models ◽  
Structural Mechanism ◽  
Faculty Hiring ◽  
Network Characteristics ◽  
Institutional Prestige ◽  
Structural Mechanisms ◽  
Global And Local ◽  
Global Placement ◽  
New Hire

AbstractFaculty hiring networks—who hires whose graduates as faculty—exhibit steep hierarchies, which can reinforce both social and epistemic inequalities in academia. Understanding the mechanisms driving these patterns would inform efforts to diversify the academy and shed new light on the role of hiring in shaping which scientific discoveries are made. Here, we investigate the degree to which structural mechanisms can explain hierarchy and other network characteristics observed in empirical faculty hiring networks. We study a family of adaptive rewiring network models, which reinforce institutional prestige within the hierarchy in five distinct ways. Each mechanism determines the probability that a new hire comes from a particular institution according to that institution’s prestige score, which is inferred from the hiring network’s existing structure. We find that structural inequalities and centrality patterns in real hiring networks are best reproduced by a mechanism of global placement power, in which a new hire is drawn from a particular institution in proportion to the number of previously drawn hires anywhere. On the other hand, network measures of biased visibility are better recapitulated by a mechanism of local placement power, in which a new hire is drawn from a particular institution in proportion to the number of its previous hires already present at the hiring institution. These contrasting results suggest that the underlying structural mechanism reinforcing hierarchies in faculty hiring networks is a mixture of global and local preference for institutional prestige. Under these dynamics, we show that each institution’s position in the hierarchy is remarkably stable, due to a dynamic competition that overwhelmingly favors more prestigious institutions. These results highlight the reinforcing effects of a prestige-based faculty hiring system, and the importance of understanding its ramifications on diversity and innovation in academia.

scholarly journals Blue reflectance in tarantulas is evolutionarily conserved despite nanostructural diversity

2015 ◽  
Vol 1 (10) ◽  
pp. e1500709 ◽  
Author(s):  
Bor-Kai Hsiung ◽  
Dimitri D. Deheyn ◽  
Matthew D. Shawkey ◽  
Todd A. Blackledge
Keyword(s):  
Sexual Selection ◽  
Phylogenetic Reconstruction ◽  
Blue Color ◽  
Structural Mechanism ◽  
Multilayer Nanostructures ◽  
Structural Colors ◽  
Color Differences ◽  
Structural Mechanisms ◽  
20 Nm ◽  
Blue Coloration

Slight shifts in arrangement within biological photonic nanostructures can produce large color differences, and sexual selection often leads to high color diversity in clades with structural colors. We use phylogenetic reconstruction, electron microscopy, spectrophotometry, and optical modeling to show an opposing pattern of nanostructural diversification accompanied by unusual conservation of blue color in tarantulas (Araneae: Theraphosidae). In contrast to other clades, blue coloration in phylogenetically distant tarantulas peaks within a narrow 20-nm region around 450 nm. Both quasi-ordered and multilayer nanostructures found in different tarantulas produce this blue color. Thus, even within monophyletic lineages, tarantulas have evolved strikingly similar blue coloration through divergent mechanisms. The poor color perception and lack of conspicuous display during courtship of tarantulas argue that these colors are not sexually selected. Therefore, our data contrast with sexual selection that typically produces a diverse array of colors with a single structural mechanism by showing that natural selection on structural color in tarantulas resulted in convergence on similar color through diverse structural mechanisms.

scholarly journals A structural mechanism for directing inverse agonism of PPARγ

2018 ◽  
Author(s):  
Richard Brust ◽  
Jinsai Shang ◽  
Jakob Fuhrmann ◽  
Jared Bass ◽  
Andrew Cano ◽  
...  
Keyword(s):  
Bound State ◽  
Inverse Agonist ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Structural Mechanism ◽  
X Ray Crystallography ◽  
Inverse Agonism ◽  
Orthosteric Ligands ◽  
Dynamics Simulations ◽  
Structural Mechanisms

AbstractSmall chemical modifications can have significant effects on ligand efficacy and receptor activity, but the underlying structural mechanisms can be difficult to predict from static crystal structures alone. Here we show how a simple phenyl-to-pyridyl substitution between two common covalent orthosteric ligands targeting peroxisome proliferator-activated receptor gamma (PPARγ) converts a transcriptionally neutral antagonist (GW9662) into an inverse agonist (T0070907). X-ray crystallography, molecular dynamics simulations, and mutagenesis coupled to activity assays reveal a water-mediated hydrogen bond network linking the T0070907 pyridyl group to Arg288 that is essential for inverse agonism. NMR spectroscopy reveals that PPARγ exchanges between two long-lived conformations when bound to T0070907 but not GW9662, including a conformation that prepopulates a corepressor-bound state, priming PPARγ for high affinity corepressor binding. Our findings demonstrate that ligand engagement of Arg288 may provide new routes for developing PPARγ inverse agonist.

scholarly journals Talin-activated vinculin interacts with branched actin networks to initiate bundles

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Rajaa Boujemaa-Paterski ◽  
Bruno Martins ◽  
Matthias Eibauer ◽  
Charlie T Beales ◽  
Benjamin Geiger ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Electron Tomography ◽  
Surface Patterning ◽  
Actin Network ◽  
Actin Bundle ◽  
Mechanical Coupling ◽  
Actin Networks ◽  
Cryo Electron Tomography ◽  
Mixed Polarity ◽  
Rapid Binding

Vinculin plays a fundamental role in integrin-mediated cell adhesion. Activated by talin, it interacts with diverse adhesome components, enabling mechanical coupling between the actin cytoskeleton and the extracellular matrix. Here we studied the interactions of activated full-length vinculin with actin and the way it regulates the organization and dynamics of the Arp2/3 complex-mediated branched actin network. Through a combination of surface patterning and light microscopy experiments we show that vinculin can bundle dendritic actin networks through rapid binding and filament crosslinking. We show that vinculin promotes stable but flexible actin bundles having a mixed-polarity organization, as confirmed by cryo-electron tomography. Adhesion-like synthetic design of vinculin activation by surface-bound talin revealed that clustered vinculin can initiate and immobilize bundles from mobile Arp2/3-branched networks. Our results provide a molecular basis for coordinate actin bundle formation at nascent adhesions.

scholarly journals Phosphorylation represses Ets-1 DNA binding by reinforcing autoinhibition

2000 ◽  
Vol 14 (3) ◽  
pp. 366-376 ◽  
Author(s):  
Dale O. Cowley ◽  
Barbara J. Graves
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Inhibitory Effect ◽  
Dna Binding Domain ◽  
Structural Elements ◽  
Binding Assays ◽  
Control Of Gene Expression ◽  
Structural Mechanism ◽  
Calcium Dependent ◽  
Dependent Inhibition

Phosphorylation of transcription factors is a key link between cell signaling and the control of gene expression. Here we report that phosphorylation regulates DNA binding of the Ets-1 transcription factor by reinforcing an autoinhibitory mechanism. Quantitative DNA-binding assays show that calcium-dependent phosphorylation inhibits Ets-1 DNA binding 50-fold. The four serines that mediate this inhibitory effect are distant from the DNA-binding domain but near structural elements required for autoinhibition. Mutational analyses demonstrate that an intact inhibitory module is required for phosphorylation-dependent regulation. Partial proteolysis studies indicate that phosphorylation stabilizes an inhibitory conformation. These findings provide a structural mechanism for phosphorylation-dependent inhibition of Ets-1 DNA binding and demonstrate a new function for inhibitory modules as structural mediators of negative signaling events.

3-D examination of the cytoskeletal sheets of mammalian eggs

1992 ◽  
Vol 50 (1) ◽  
pp. 914-915
Author(s):  
Carolyn A. Larabell ◽  
David G. Capco ◽  
G. Ian Gallicano ◽  
Robert W. McGaughey ◽  
Karsten Dierksen ◽  
...  
Keyword(s):  
Actin Filaments ◽  
Somatic Cells ◽  
Freeze Fracture ◽  
Blastocyst Stage ◽  
Cell Cytoplasm ◽  
Planar Structures ◽  
Cytoskeletal Network ◽  
Entire Cell ◽  
Cytoskeletal Networks ◽  
Mammalian Eggs

Mammalian eggs and embryos contain an elaborate cytoskeletal network of “sheets” which are distributed throughout the entire cell cytoplasm. Cytoskeletal sheets are long, planar structures unlike the cytoskeletal networks typical of somatic cells (actin filaments, microtubules, and intermediate filaments), which are filamentous. These sheets are not found in mammalian somatic cells nor are they found in nonmammalian eggs or embryos. Evidence that they are, indeed, cytoskeletal in nature is derived from studies demonstrating that 1) the sheets are retained in the detergent-resistant cytoskeleton fraction; 2) there are no associated membranes (determined by freeze-fracture); and 3) the sheets dissociate into filaments at the blastocyst stage of embryogenesis. Embedment-free sections of hamster eggs viewed at 60 kV show sheets running across the egg cytoplasm (Fig. 1). Although this approach provides excellent global views of the sheets and their reorganization during development, the mechanism of image formation for embedment-free sections does not permit evaluation of the sheets at high resolution.

Structural phenomena in the growth of carbon nanotubes

1993 ◽  
Vol 51 ◽  
pp. 750-751
Author(s):  
Jun Jiao
Keyword(s):  
Carbon Nanotubes ◽  
Growth Mechanism ◽  
Carbonaceous Material ◽  
Cluster Growth ◽  
Structural Elements ◽  
Rich Variety ◽  
Different Shapes ◽  
Point To Point

HREM studies of the carbonaceous material deposited on the cathode of a Huffman-Krätschmer arc reactor have shown a rich variety of multiple-walled nano-clusters of different shapes and forms. The preparation of the samples, as well as the variety of cluster shapes, including triangular, rhombohedral and pentagonal projections, are described elsewhere.The close registry imposed on the nanotubes, focuses attention on the cluster growth mechanism. The strict parallelism in the graphitic separation of the tube walls is maintained through changes of form and size, often leading to 180° turns, and accommodating neighboring clusters and defects. Iijima et. al. have proposed a growth scheme in terms of pentagonal and heptagonal defects and their combinations in a hexagonal graphitic matrix, the first bending the surface inward, and the second outward. We report here HREM observations that support Iijima’s suggestions, and add some new features that refine the interpretation of the growth mechanism. The structural elements of our observations are briefly summarized in the following four micrographs, taken in a Hitachi H-8100 TEM operating at an accelerating voltage of 200 kV and with a point-to-point resolution of 0.20 nm.

Designing TIMP (tissue inhibitor of metalloproteinases) variants that are selective metalloproteinase inhibitors

2003 ◽  
Vol 70 ◽  
pp. 201-212 ◽  
Author(s):  
Hideaki Nagase ◽  
Keith Brew
Keyword(s):  
Three Dimensional ◽  
Therapeutic Interventions ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Structural Basis ◽  
Structural Elements ◽  
Ridge Structure ◽  
Extracellular Matrix Components ◽  
Metalloproteinase Inhibitors ◽  
The Matrix ◽  
A Disintegrin And Metalloproteinase

The tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of the matrix metalloproteinases (MMPs), enzymes that play central roles in the degradation of extracellular matrix components. The balance between MMPs and TIMPs is important in the maintenance of tissues, and its disruption affects tissue homoeostasis. Four related TIMPs (TIMP-1 to TIMP-4) can each form a complex with MMPs in a 1:1 stoichiometry with high affinity, but their inhibitory activities towards different MMPs are not particularly selective. The three-dimensional structures of TIMP-MMP complexes reveal that TIMPs have an extended ridge structure that slots into the active site of MMPs. Mutation of three separate residues in the ridge, at positions 2, 4 and 68 in the amino acid sequence of the N-terminal inhibitory domain of TIMP-1 (N-TIMP-1), separately and in combination has produced N-TIMP-1 variants with higher binding affinity and specificity for individual MMPs. TIMP-3 is unique in that it inhibits not only MMPs, but also several ADAM (a disintegrin and metalloproteinase) and ADAMTS (ADAM with thrombospondin motifs) metalloproteinases. Inhibition of the latter groups of metalloproteinases, as exemplified with ADAMTS-4 (aggrecanase 1), requires additional structural elements in TIMP-3 that have not yet been identified. Knowledge of the structural basis of the inhibitory action of TIMPs will facilitate the design of selective TIMP variants for investigating the biological roles of specific MMPs and for developing therapeutic interventions for MMP-associated diseases.

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