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High-resolution structures of tau filaments shed light on the ultrastructure of neurofibrillary lesions in Alzheimer’s disease.

Schweighauser, Shi, Murzin and colleagues report cryo-EM structures of tau filaments from individuals with P301L or P301T MAPT mutations. P301L tau filaments adopted a distinct three-lobed fold, while P301T filaments had either a variant of the three-lobed fold or a V-shaped fold.

Qi et al. used cryo-electron microscopy to determine the structures of tau filaments from the brains of individuals with MAPT mutants V337M and R406W, known to give rise to frontotemporal dementias. They showed that the tau filaments adopted the Alzheimer fold.

A time-resolved cryogenic electron microscopy analysis provides structural information on the processes of primary and secondary nucleation of tau amyloid formation, with implications for the development of new therapies.

A study using structure determination by cryogenic electron microscopy identifies and characterizes TMEM106B amyloid filaments in human brain, and suggests that their formation is age dependent, with no obvious association with disease.

The authors report on the structures of α-synuclein filaments from the brains of individuals with Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies and how they differ from those seen in multiple system atrophy.

Cryo-electron microscopy structures of tau filaments from progressive supranuclear palsy and other tauopathies reveal new filament conformations, and suggest that tauopathies can be classified on several different levels according to their filament folds.

Cyro-electron microscopy of tau filaments from people with corticobasal degeneration reveals a previously unseen four-layered fold, distinct from the filament structures seen in Alzheimer’s disease, Pick’s disease and chronic traumatic encephalopathy.

Cryo-electron microscopy reveals the structures of α-synuclein filaments from the brains of individuals with multiple system atrophy.

Amyloid-β peptides and tau proteins form filaments in the brain in Alzheimer’s disease. Using an electron microscopy approach to visualize thin slices of brain tissue in 3D, these filaments can be seen in their native environment.

Blush regularization makes use of a neural network pre-trained on a diverse set of high-resolution cryo-EM half-maps to improve image alignment, effectively lowering the size barrier, during cryo-EM structure determination.

Advances in electron cryo-microscopy hardware allow proteins to be studied at atomic resolution.

DynaMight models continuous structural heterogeneity in cryo-EM datasets, leading to an improved reconstruction of the consensus structure. The study also explores the issue of overfitting when modeling structural flexibility.

The structures of tau filaments from patients with the neurodegenerative disorder Pick’s disease show that the filament fold is different from that of the tau filaments found in Alzheimer’s disease.

Cryo-electron microscopy structures of tau filaments from the brains of three individuals with chronic traumatic encephalopathy reveal distinct assembled tau conformers, with a novel protofilament fold enclosing hydrophobic molecules.

ModelAngelo builds atomic models and identifies proteins with unknown sequences in cryo-EM maps.

The bacterial zinc transporter ZntB is important for maintaining zinc homeostasis and is mechanistically not well understood. Here, the authors present the cryo-EM structure of ZntB at 4.2 Å resolution, perform transport assays and propose a model for its Zn²⁺ transport mechanism.

Cryo-EM reveals one mechanism of action of the antimalarial mefloquine: mefloquine binds to the Plasmodium falciparum 80S ribosome, inhibiting protein synthesis in the parasite.

Using electron cryomicroscopy, the structure of the closed-state rabbit ryanodine receptor RyR1 in complex with its modulator FKBP12 is solved at 3.8 Å; in addition to determining structural details of the ion-conducting channel domain, three previously uncharacterized domains help to reveal a molecular scaffold that allows long-range allosteric regulation of channel activities.

The three-dimensional structure of intact human γ-secretase complex at 4.5 Å resolution is revealed by cryo-electron-microscopy single-particle analysis; the complex comprises a horseshoe-shaped transmembrane domain containing 19 transmembrane segments, and a large extracellular domain from nicastrin, which sits immediately above the hollow space formed by the horseshoe.

Cryo-electron microscopy of the tripartite MacA–MacB–TolC multidrug transporter.

The structure of the multiprotein Fanconi anaemia core complex, determined using cryo-electron microscopy and mass spectrometry, shows that the complex adopts an extended asymmetric structure and highlights the structural and functional asymmetry of the RING finger domains.

Precision design of DNA origami needs precision validation. Here, the authors developed cryo-EM methods for obtaining high resolution structural data and for constructing pseudo-atomic models in a semi-automated fashion, allowing for iterative nanodevice inspection and refinement.

The SARS-CoV-2 spike glycoprotein is flexible, and its receptor-binding domain (RBD) fluctuates between open and closed conformations. Disulfide bonds are engineered into the spike ectodomain to lock the RBD in the closed state, leading to a construct with high thermostability.

The atomic structure of human γ-secretase at 3.4 Å resolution, determined by single-particle cryo-electron microscopy.

Cryo-electron microscopy and tomography studies reveal the structures, conformations and distributions of spike protein trimers on intact severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virions and provide a basis for understanding the interactions of the spike protein with neutralizing antibodies.

This study determines the structure of the spliceosomal tri-snRNP complex (containing three small nuclear RNAs and more than 30 proteins) by single-particle cryo-electron microscopy; the resolution is sufficient to discern the organization of RNA and protein components involved in spliceosome activation, exon alignment and catalysis.

Type II chaperonins, such as CCT, and Hsp70 class chaperones, such as Hsc70, have crucial roles in protein folding and share some substrate overlap. Structural data now indicate that a complex forms between the β subunit of CCT and Hsc70, suggesting a coordinated hand-off mechanism for substrate interactions.

EM analyses reveal the three-dimensional structure of human telomerase. Along with functional biochemistry data, the work reveals that telomerase is dimeric in its active form. Each of the two TERT subunits can bind telomeric DNA substrates, and both active sites are required for function.

A 3.7 Å resolution structure for the yeast U4/U6.U5 tri-snRNP, a complex involved in splicing, allows a better appreciation of the architecture of the tri-snRNP, and offers new functional insights into the activation of the spliceosome and the assembly of the catalytic core.

Cryo-EM and NMR analyses of the E. coli replisome show how DNA-end fraying after mismatch incorporation at the polymerase active site enables substrate ends to reach the ‘proofreading’ exonuclease site for mismatch removal.

Cryo-EM analyses provide a near-atomic view of the C. elegans securin–separase complex, with insights into the mechanism by which securin inhibits separase's protease activity.

This report describes the outcomes of the Data Management Challenges in 3D Electron Microscopy workshop. Key topics discussed include data models, validation and raw-data archiving. The meeting participants agreed that the EMDataBank should take the lead in addressing these issues, and concrete action points were agreed upon that will have a substantial impact on the accessibility of three-dimensional EM data in biology and medicine.

Structural studies of amyloid filaments purified from brains of people with neurodegenerative diseases link specific amyloid folds with distinct diseases and provide a basis for the development of models of neurodegenerative disease.

Electron cryo-tomography produces 3D pictures of unique objects such as viruses, organelles or cells. This is a protocol for macromolecular structure determination from tomographic data using subtomogram averaging in the RELION software.