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Clathrin forms diverse lattice and cage structures that change size and shape rapidly in response to the needs of eukaryotic cells during clathrin-mediated endocytosis and intracellular trafficking. We present the cryo-EM structure and molecular model of assembled porcine clathrin, providing insights into interactions that stabilize key elements of the clathrin lattice, namely, between adjacent heavy chains, at the light chain–heavy chain interface and within the trimerization domain. Furthermore, we report cryo-EM maps for five different clathrin cage architectures. Fitting structural models to three of these maps shows that their assembly requires only a limited range of triskelion leg conformations, yet inherent flexibility is required to maintain contacts. Analysis of the protein–protein interfaces shows remarkable conservation of contact sites despite architectural variation. These data reveal a universal mode of clathrin assembly that allows variable cage architecture and adaptation of coated vesicle size and shape during clathrin-mediated vesicular trafficking or endocytosis.

Waltz is a position-specific amyloid-propensity prediction tool developed to distinguish between true amyloid sequences and amorphous β-aggregates. Protein aggregation results in β-sheet–like assemblies that adopt either a variety of amorphous morphologies or ordered amyloid-like structures. These differences in structure also reflect biological differences; amyloid and amorphous β-sheet aggregates have different chaperone affinities, accumulate in different cellular locations and are degraded by different mechanisms. Further, amyloid function depends entirely on a high intrinsic degree of order. Here we experimentally explored the sequence space of amyloid hexapeptides and used the derived data to build Waltz, a web-based tool that uses a position-specific scoring matrix to determine amyloid-forming sequences. Waltz allows users to identify and better distinguish between amyloid sequences and amorphous β-sheet aggregates and allowed us to identify amyloid-forming regions in functional amyloids.

Controlling the order and spatial distribution of self-assembly in multicomponent supramolecular systems could underpin exciting new functional materials, but it is extremely challenging. When a solution of different components self-assembles, the molecules can either coassemble, or self-sort, where a preference for like-like intermolecular interactions results in coexisting, homomolecular assemblies. A challenge is to produce generic and controlled ‘one-pot’ fabrication methods to form separate ordered assemblies from ‘cocktails’ of two or more self-assembling species, which might have relatively similar molecular structures and chemistry. Self-sorting in supramolecular gel phases is hence rare. Here we report the first example of the pH-controlled self-sorting of gelators to form self-assembled networks in water. Uniquely, the order of assembly can be predefined. The assembly of each component is preprogrammed by the p K a of the gelator. This pH-programming method will enable higher level, complex structures to be formed that cannot be accessed by simple thermal gelation. The fabrication self-sorting supramolecular gels, containing co-existing homomolecular assemblies with similar physical and chemical properties, is challenging. Here pH-controlled self-sorting gelators are reported, where the order of assembly of each component is predetermined by gelator p K a .

Soluble guanylate cyclase (sGC) is the primary receptor for nitric oxide (NO) in mammalian nitric oxide signaling. We determined structures of full-length Manduca sexta sGC in both inactive and active states using cryo-electron microscopy. NO and the sGC-specific stimulator YC-1 induce a 71° rotation of the heme-binding β H-NOX and PAS domains. Repositioning of the β H-NOX domain leads to a straightening of the coiled-coil domains, which, in turn, use the motion to move the catalytic domains into an active conformation. YC-1 binds directly between the β H-NOX domain and the two CC domains. The structural elongation of the particle observed in cryo-EM was corroborated in solution using small angle X-ray scattering (SAXS). These structures delineate the endpoints of the allosteric transition responsible for the major cyclic GMP-dependent physiological effects of NO. In humans and other animals, as the heart pumps blood around the body, the blood exerts pressure on the walls of the blood vessels, much like water flowing through a hose. Our blood pressure naturally varies over the day, generally increasing when we are active and decreasing when we rest. However, if blood pressure remains high for extended periods of time it can lead to heart attacks, strokes and other serious health conditions. In 2013, a new drug known as Adempas was approved to treat high blood pressure in the lungs. This drug helps a signaling molecule in the body called nitric oxide to activate an enzyme that widens blood vessels and in turn lower blood pressure. Previous studies have found that the enzyme – called soluble guanylate cyclase (sGC) – contains several distinct domains and that nitric oxide binds to a domain known as β H-NOX. However, it was not clear how β H-NOX and the other three domains fit together to make the three-dimensional structure of the enzyme, or how nitric oxide and Adempas activate it. To address this question, Horst, Yokom et al. used a technique called cryo-electron microscopy to determine the three-dimensional structures of the inactive and active forms of a soluble guanylate cyclase from a moth known as Manduca sexta. To produce the active form of the enzyme, soluble guanylate cyclase was incubated with both nitric oxide and a molecule called YC-1 that works in similar way to Adempas. The structures revealed that nitric oxide and YC-1 caused β H-NOX and another domain to rotate by 71. This in turn caused the remaining two domains – known as the coiled-coil domains – to change shape, and all of these movements together led to the activated enzyme. The structures also revealed that YC-1 bound to a site on the enzyme between β H-NOX and the coiled-coil domains. Understanding how a drug for a particular condition works makes it much easier to develop new drugs that are more effective at treating the same condition or are tailored to treat other diseases. Therefore, these findings will allow pharmaceutical companies and other organizations to develop new drugs for high blood pressure and other cardiovascular diseases in a much more precise way.

MiDAC is one of seven distinct, large multi-protein complexes that recruit class I histone deacetylases to the genome to regulate gene expression. Despite implications of involvement in cell cycle regulation and in several cancers, surprisingly little is known about the function or structure of MiDAC. Here we show that MiDAC is important for chromosome alignment during mitosis in cancer cell lines. Mice lacking the MiDAC proteins, DNTTIP1 or MIDEAS, die with identical phenotypes during late embryogenesis due to perturbations in gene expression that result in heart malformation and haematopoietic failure. This suggests that MiDAC has an essential and unique function that cannot be compensated by other HDAC complexes. Consistent with this, the cryoEM structure of MiDAC reveals a unique and distinctive mode of assembly. Four copies of HDAC1 are positioned at the periphery with outward-facing active sites suggesting that the complex may target multiple nucleosomes implying a processive deacetylase function. The MiDAC complex recruits class I histone deacetylases to chromatin but little is known about its precise structure and function. Here, the authors explore the role of MiDAC in the cell cycle and during mouse embryogenesis, and present cryoEM structures that provide insight into MiDAC’s mode of assembly.

In recent years, there have been a number of popular robotics competitions whose intent is to advance the state of research by comparing embodied entries against one another in real time. The IEEE Humanoid application challenge is intended to broaden these by allowing more open ended entries, with a general theme within which entrants are challenged to create the most effective application involving a humanoid robot. This year’s theme was Robot Magic, and this paper describes our first-place winning entry in the 2017 competition, running on a ROBOTIS OP2 humanoid robot. We describe the overall agent design and contributions to perception, learning, control, and representation, together supporting a robust live robot magic performance.

The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities. The complex regulates the higher-order structure of chromatin, and has important roles in the regulation of gene expression, DNA damage repair and cell differentiation. HDACs 1 and 2 are recruited by the MTA1 corepressor to form the catalytic core of the complex. The histone chaperone protein RBBP4, has previously been shown to bind to the carboxy-terminal tail of MTA1. We show that MTA1 recruits a second copy of RBBP4. The crystal structure reveals an extensive interface between MTA1 and RBBP4. An EM structure, supported by SAXS and crosslinking, reveals the architecture of the dimeric HDAC1:MTA1:RBBP4 assembly which forms the core of the NuRD complex. We find evidence that in this complex RBBP4 mediates interaction with histone H3 tails, but not histone H4, suggesting a mechanism for recruitment of the NuRD complex to chromatin. The correct regulation of our genes is essential for life. Genes are actively switched on or off through the action of assemblies of proteins that act together as molecular machines. Some of these machines alter the way that DNA is packaged inside cells. Packaged DNA – called chromatin – consists of DNA wrapped around proteins called histones, which together form structures called nucleosomes. Changing how tightly nucleosomes are packed together can alter whether a gene is active: tighter packing makes it harder to access the genes in that stretch of DNA and therefore inactivates them. In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. Understanding how protein complexes are assembled tells us a lot about how they work. Millard et al. have therefore used a number of structural techniques to investigate the three-dimensional architecture of the three core proteins in the NuRD complex. The resulting structures have revealed how the HDAC1, MTA1 and RBBP4 proteins interact to influence how the complex is recruited to nucleosomes. The next step will be to assemble all the remaining proteins of the NuRD complex to understand its architecture as a whole.

Abstract Motivation The electron microscopy data bank (EMDB) is a key repository for three-dimensional electron microscopy (3DEM) data but lacks comprehensive annotations and connections to many related biological, functional, and structural data resources. This limitation arises from the optional nature of such information to reduce depositor burden and the complexity of maintaining up-to-date external references, often requiring depositor consent. To address these challenges, we developed EMDB Integration with Complexes, Structures, and Sequences (EMICSS), an independent system that automatically updates cross-references with over 20 external resources, including UniProt, AlphaFold DB, PubMed, Complex Portal, and Gene Ontology. Results EMICSS (https://www.ebi.ac.uk/emdb/emicss) annotations are accessible in multiple formats for every EMDB entry and its linked resources, and programmatically via the EMDB application programming interface. EMICSS plays a crucial role supporting the EMDB website, with annotations being used on entry pages, statistics, and in the search system. Availability and implementation EMICSS is implemented in Python and it is an open-source, distributed under the Apache license version 2.0, with core code available on GitHub (https://github.com/emdb-empiar/added_annotations).

Learning meaningful representations of images in scientific domains that are robust to variations in centroids and orientations remains an important challenge. Here we introduce centroid- and orientation-aware disentangling autoencoder (CODAE), an encoder–decoder-based neural network that learns meaningful content of objects in a latent space. Specifically, a combination of a translation- and rotation-equivariant encoder, Euler encoding and an image moment loss enables CODAE to extract features invariant to positions and orientations of objects of interest from randomly translated and rotated images. We evaluate this approach on several publicly available scientific datasets, including protein images from life sciences, four-dimensional scanning transmission electron microscopy data from material science and galaxy images from astronomy. The evaluation shows that CODAE learns centroids, orientations and their invariant features and outputs, as well as aligned reconstructions and the exact view reconstructions of the input images with high quality. Cha and colleagues present a translation- and rotation-equivariant autoencoder-based method for robust image recognition, which they demonstrate on diverse tasks from bioinformatics, material science and astronomy.

Carbon fiber reinforced composites have become a material of interest in various high-performance sectors such as aerospace and automotive applications due to their high stiffness to strength ratio, allowing for improved durability and energy saving. Typically, carbon fiber reinforced composites are made with continuous carbon fiber which imposes limitations on manufacturability due to inextensibility of the fibers. Highly aligned discontinuous fiber (ADF) composites have been shown to achieve aerospace-grade properties and have the additional advantage to stretch form biaxially to complex geometries. This thesis focuses on evaluating the formability of ADF composites utilizing Tailored Universal Feedstock for Forming (TuFF) aligned fibers combined with thermoplastic and thermoset resin systems. The primary aim is to establish a comprehensive process-structure-property relationships for ADF composites through novel methodologies for defining forming limits and characterizing material performance. A novel aligned discontinuous fiber forming limit diagram (ADF-FLD) was developed to define formability for this class of material relative to material orientation. Methodologies were developed to construct a forming limit diagram (FLD) for ADF composites, providing a detailed framework for strain mode forming limits based on lamina fiber orientation and a predicted thickness variability in a closed mold and an open mold forming process. To demonstrate this, ADF composite blanks were stretch formed to various strain levels and modes (longitudinal plane strain, transverse plane strain, and biaxial plane strain), while employing both in situ and ex situ techniques to measure deformation. By manipulating surface ply orientations of ADF laminates (0, 45, or 90 degrees) relative to the major strain direction, different strain modes were imposed and measured using photogrammetry post forming and digital image correlation (DIC) for real time strain analysis.First, a method was developed to characterize deformation of multiaxial thermoplastic TuFF laminates in a series of closed molds at various strain levels, using a double diaphragm gas bulge forming process and photogrammetry to analyze strains post forming. A first-order failure definition based on a predicted thickness coefficient of variation relative to average strain was employed to evaluate the forming limits of the material and populate an ADF-FLD, describing the formability of the ADF composite.Additionally, a method was devised to characterize the deformation response of multiaxial thermoset TuFF laminates in diaphragm forming for longitudinal and transverse plane strain. Using a gas bulge method and an Interlaken SP75 highly instrumented forming press, high fidelity strain measurements were obtained via an in situ 3D digital image correlation system. This method allowed for real-time recording of surface strains, allowing for progression of strain variability to be measured continuously. The same failure criterion was applied to the strain data, and an ADFFLD was constructed with repeatable results for each strain mode.Overall, this thesis provides a comprehensive methodology and experimental framework for defining forming limits and optimizing the stretch forming process of ADF composites. The outcomes offer significant insights into the material and process variables, crucial for the design and manufacturing of complex composite parts in aerospace and other high-performance applications.