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Degenerative diseases such as Alzheimer's or Parkinson's are associated with the misfolding of many diverse proteins, yet the amyloid fibrils formed by all these proteins are similar. David Eisenberg and colleagues have now identified 30 short fibril-forming peptides implicated in a range of amyloid diseases and have solved 13 of their atomic structures, revealing variations in one common feature — the 'steric zipper'.

Cryo-electron and atomic force microscopy shed light on how fibrils of the protein tau, which accumulate in the brain of people with Alzheimer’s disease, can be disassembled by short peptides, providing a possible route towards developing treatments.

Fragmentation of large, imperfect crystals into nanocrystals by sonication, vortexing, or vigorous pipetting facilitates atomic-resolution analysis by the cryo-EM method MicroED.

An environmentally safe means of mosquito control is the application of Bacillus thuringiensis israelensis, which produces a cocktail of four naturally crystalline proteins exclusively toxic to mosquito. Here the authors report the atomic-resolution structures of Bti Cry11Aa and related Btj Cry11Ba solved de novo through Serial Femtosecond Crystallography on naturally-occurring nanocrystals.

A cell free or synthetic biochemistry approach offers a way to circumvent the many constraints of living cells. Here, the authors demonstrate, via enzyme and process enhancements, the production of isobutanol with the metrics exceeding highly developed ethanol fermentation.

In plants and fungi, cellular ion homeostasis is powered by the proton pump, a member of the P-type ATPase family. The first X-ray structure of the H⁺-ATPase is presented, and insight into the mechanism by which protons are transported against an electrochemical gradient is provided.

Natural killer cells and cytotoxic T cells kill virus-infected and malignant cells, releasing the pore-forming protein perforin in the process. Perforin is required for the delivery of pro-apoptotic granzymes to the target cell. These authors present the crystal structure of a perforin monomer together with a cryo-electron microscopy reconstruction of the oligomeric pore. Perforin monomers within the pore are arranged with an inside-out orientation relative to the structurally homologous monomers of cholesterol-dependent cytolysins.

The structure of the bacterial toxin BinAB, which is used to combat mosquito-borne diseases, reveals pH-sensitive switches and carbohydrate-binding modules that may contribute to the larvicidal function of the toxin.

Murray et al. report an approach to identify pathogenic mutations in low-complexity-domain-containing proteins that lead to the formation of amyloid aggregates. Among those characterized are keratin-8 mutations associated with liver disease, linking amyloid aggregation to liver pathology.

Human islet amyloid polypeptide (hIAPP) is a protein commonly forming aggregates in islet cells of those afflicted by type II diabetes. New structures of fibrils seeded with patient-derived material reveal a diverse repertoire of structures, some of which may resemble those appearing in vivo.

Prions can adopt a transmissible β-sheet-rich conformation and also form strains with different structural and biological properties. Polymorphic crystal structures of peptides from prion- and other amyloid-forming proteins suggest the structural basis for prion strains, revealing two potential mechanisms: packing and segmental polymorphism.

In this work, the authors report Cryo-EM imaging revealing diversity in amyloid fibril structures among ATTR patients with the same genetic mutation I84S. Further study is warranted to grasp the implications in ATTR amyloidosis pathology.

A short segment of α-synuclein called NACore (residues 68–78) is responsible for the formation of amyloid aggregates responsible for cytotoxicity in Parkinson disease; here the nanocrystal structure of this invisible-to-optical-microscopy segment is determined using micro-electron diffraction, offering insight into its function and simultaneously demonstrating the first use of micro-electron diffraction to solve a previously unknown protein structure.

Amyloid fibrils extracted from brains of patients with frontotemporal lobar degeneration with TAR DNA-binding-protein immunoreactivity (FTLD-TDP) are made up of transmembrane protein 106B.

hnRNPA2 is involved in RNA metabolism and can form both functional amyloid-like fibrils in membraneless organelles, and pathogenic fibrils in neurodegenerative conditions. Here, the authors present the cryo-EM fibril structure of the wild-type hnRNPA2 low-complexity domain (LCD) and the crystal structure of a LCD segment with the disease causing D290V variant and discuss how mutations can transform fibril structure from a functional to a pathogenic form.

Evidence suggests that fibrous aggregates of protein tau may be the proximal cause of Alzheimer’s disease. Here, using atomic structures of tau fibrils from brains of people with Alzheimer’s disease, the authors have found small-molecule drug leads that disaggregate tau fibrils in vitro.

Segments from TDP-43 LCD form irreversible steric zippers typical of amyloid fibrils and labile interactions found in reversible assemblies. Familial ALS mutations or a phosphorylation event can convert reversible to irreversible aggregates.

Current guidelines recommend stereotactic radiosurgery for brain metastasis measuring less than 3 cm but there is significant variability in outcomes following treatment. This study shows that in treatment naïve brain metastasis less than 3 cm, intrinsic biological differences across multiple histologies may influence response to stereotactic radiosurgery.

β2-microglobulin can form different forms of amyloid fibrils within joints of dialysis patients. Now the crystal structures of a β2m domain swapped dimer and of the steric zipper formed by a short peptide indicate how these fibrils might form.

A set of GFP fusions with as few as 12 residues appended to the C terminus is shown to assemble into filaments in E. coli. Crystal structures reveal a mechanism termed ‘runaway domain coupling’ and illustrate how protein filament formation can evolve.

In patients with sporadic Alzheimer’s disease part of the Asp23 residues are isomerized to L-isoaspartate (L-isoAsp23). Here the authors present the MicroED structures of wild-type and L-isoAsp23 Aβ 20–34 amyloid fibrils that both form tightly packed cores and self-associate through two distinct interfaces with one of these interfaces being strengthened by the isoaspartyl modification.

Cryo-EM structures of fibrils formed by two segments from TDP-43 that are essential for aggregation of the full-length protein reveal fibril polymorphism and suggest mechanisms for pathogenesis.

A cryo-EM structure of in vitro−formed fibrils of the human islet amyloid polypeptide (hIAPP) suggests both why the mutation S20G promotes aggregation and a potential basis for cross-seeding with β-amyloid, and leads to the design of peptide inhibitors.

Here, the authors show the amyloid formation of a low-complexity domain of NCAP, and its potential for guiding the design of antiviral agents.

A cryo-EM structure of a stable, protease-resistant fibril formed by a fragment of the human prion protein shows two intertwined protofilaments with a tightly packed hydrophobic interface.

Bacillus thuringiensis israelensis (Bti) produces the naturally-crystalline proteinaceous toxin Cyt1Aa that is toxic to mosquito larvae. Here the authors grow recombinant nanocrystals of the Cyt1Aa protoxin in vivo and use serial femtosecond crystallography to determine its structure at different redox and pH conditions and by combining their structural data with further biochemical, toxicological and biophysical analyses provide mechanistic insights into the Cyt1Aa bioactivation cascade.

Cryo-EM analyses of α-synuclein fibrils formed with hereditary Parkinson’s disease mutant H50Q reveal features that help explain the mutant’s properties in vitro and in cells.

Structural analyses of fibrils formed by segments from human TDP-43 RRM2 reveal extensive packing and positional polymorphism.

The intrinsically disordered protein alpha-synuclein (aSyn) forms polymorphic fibrils. Here the authors provide molecular insights into aSyn fibril polymorphism and present the cryo-EM structures of the two predominant species, a rod and a twister both determined at 3.7 Å resolution.

Directed evolution of the final enzyme in the lovastatin biosynthetic pathway yields a variant with 29 mutations that does not require a carrier protein and displays altered dynamics of the catalytic residues, spending more time in the catalytically active conformation.

Inhibiting the interaction between amyloid-β (Aβ) and a neuronal cell surface receptor, LilrB2, could offer a potential route for treating Alzheimer’s disease. Now, binding sites between Aβ and LilrB2 have been discovered and computational selection has identified inhibitors that block this binding site. Cell-penetrating inhibitors were found to block the Aβ–LilrB2 interaction and limit Aβ-induced cytotoxicity.

The protein tau forms abnormal filamentous aggregates called tangles in the brains of people with neurodegeneration. Structures of two such filaments offer pathways to a deeper understanding of Alzheimer's disease. See Article p.185

Simple enzyme mimetics are highly desired for industrial settings providing high catalyst stability and low production costs. This work reports that phenylalanine and zinc ions can self-assemble into a supramolecular structure showing catalytic properties similar to those of the natural enzyme carbonic anhydrase.

DNA is an attractive nanomaterial, yet limited compared to polyamides due to low stability and mechanical issues. Here, the authors combine polyamide and DNA characteristics to form mechanically rigid self-assembled peptide nucleic acid based materials with high stiffness and Young’s modulus.

MICAL Redox enzymes post-translationally modify F-actin to promote its cellular destabilization. Here, the authors present a 3.9Å cryoEM structure of Mical-oxidized F-actin, showing its nucleotide-state dependent dynamic instability and susceptibility to cofilin-induced severing in the presence of inorganic phosphate.

MicroED structure of a peptide from the β2–α2 loop of the bank vole prion protein reveals a protofibril stabilized by a dense network of hydrogen bonds.

Electron tomography is used to create a 3D reconstruction of a tungsten needle that allows the positions of individual atoms to be localized with a precision of 19 picometres, without using averaging or assuming the sample crystallinity.

Beatrice Melin, Richard Houlston, Melissa Bondy and colleagues report results of a large-scale genome-wide association study of glioma. They identify five new risk loci for glioblastoma and eight new risk loci for non-glioblastoma tumors, highlighting distinct genetic etiologies for these two glioma subtypes.

Richard Houlston, Melissa Bondy and colleagues identify variants at five loci associated with glioma susceptibility, providing insights into the etiology of this primary brain tumor. The risk loci include common variants near TERT, CDKN2A-CDKN2B and RTEL1.