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Amyloid fibril structures

In this collection, we highlight papers reporting structural insights into amyloid fibrils associated with neurodegenerative and systemic diseases as well as functional amyloids that were obtained using cryo-electron microscopy (cryo-EM), NMR, X-ray crystallography and microcrystal electron diffraction. Cryo-EM also allows the structure determination of fibrils isolated from tissue samples, which revealed structural differences between ex vivo and in vitro generated fibrils and a wide spread polymorphism among amyloid fibrils.

Cryo-EM structures of ex vivo fibrils

Systemic AL amyloidosis is caused by misfolding of immunoglobulin light chains (LCs) but how post-translational modifications (PTMs) of LCs influence amyloid formation is not well understood. Here, the authors present the cryo-EM structure of an AL amyloid fibril derived from the heart tissue of a patient that is partially pyroglutamylated, N-glycosylated and contains an intramolecular disulfide bond. Based on their structure and biochemical experiments the authors conclude that the mutational changes, disulfide bond and glycosylation determine the fibril protein fold and that glycosylation protects the fibril core from proteolytic degradation.

Article | Open Access | | Nature Communications

Alzheimer’s disease is characterised by the deposition of Aβ amyloid fibrils and tau protein neurofibrillary tangles. Here the authors use cryo-EM to structurally characterise brain derived Aβ amyloid fibrils and find that they are polymorphic and right-hand twisted, which differs from in vitro generated Aβ fibrils.

Article | Open Access | | Nature Communications

Systemic AA amyloidosis is a protein misfolding disease caused by the formation of amyloid fibrils from serum amyloid A (SAA) protein. Here, the authors present the cryo-EM structures of AA amyloid fibrils isolated from mouse tissue and in vitro formed fibrils, which differ in their structures and they also show that the ex vivo fibrils are more resistant to proteolysis than the in vitro fibrils and propose that pathogenic amyloid fibrils might originate from proteolytic selection.

Article | Open Access | | Nature Communications

Systemic amyloidosis of the ATTR is one of the most abundant forms of systemic amyloidosis and caused by misfolding of the circulating blood protein transthyretin (TTR). Here the authors present the cryo-EM structure of patient-derived Val30Met ATTR amyloid fibrils which reveals that the protofilament consists of an N-terminal and a C-terminal TTR fragment and discuss implications for the mechanism of misfolding.

Article | Open Access | | Nature Communications

Systemic AA amyloidosis is caused by misfolding of the acute phase protein serum amyloid A1. Here the authors present the cryo-EM structures of murine and human AA amyloid fibrils that were isolated from tissue samples and describe how the fibrils differ in their fundamental structural properties.

Article | Open Access | | Nature Communications

Systemic AL amyloidosis is a protein misfolding disease caused by the aggregation and fibrillation of immunoglobulin light chains (LCs). Here, the authors present the cryo-EM structures of λ3 LC-derived amyloid fibrils that were isolated from patient tissue and they observe structural breaks, where the two different fibril structures co-exist at different z-axial positions within the same fibril.

Article | Open Access | | Nature Communications

Structures of in vitro generated fibrils

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) patients have brain deposits with amyloid-like aggregates from large C-terminal fragments of the transactive response DNA-binding protein of 43 kDa (TDP-43). Here, the authors present the cryo-EM structure of amyloid fibrils generated from the complete C-terminal TDP-43 low complexity domain and they discuss the effects of disease-causing mutations and phosphorylation of specific Ser residues.

Article | Open Access | | Nature Communications

Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) shuttles between the nucleus and cytoplasm to regulate gene expression and RNA metabolism and its low complexity (LC) C-terminal domain facilitates liquid–liquid phase separation and amyloid aggregation. Here, the authors present the cryo-EM structure of amyloid fibrils formed by the hnRNPA1 LC domain, which reveals that the hnRNPA1 nuclear localization sequence forms the fibril core, and they discuss how ALS-causing mutations affect fibril stability.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

The low-complexity (LC) domain mediates liquid-liquid phase separation and fibril formation of the RNA-binding protein FUS (FUsed in Sarcoma). Here, the authors combine cryo-EM, solid-state NMR measurements and MD simulations to structurally characterise the fibrils formed by the C-terminal half of the FUS LC domain and discuss stabilizing interactions within the fibril core.

Article | Open Access | | Nature Communications

The Src-homology 3 domain of phosphatidyl-inositol-3-kinase (PI3K-SH3) is a model system for studying amyloid fibril formation. Here the authors present the 3.4 Å cryo-EM structure of the PI3K-SH3 amyloid fibril, which allows them to rationalize the effects of mutations on the kinetics of fibril formation.

Article | Open Access | | Nature Communications

Impaired kidney function can lead to an increase of β2-microglobulin (β2m) serum levels, which can cause β2m aggregation and amyloid fibril formation. Here the authors combine cryo-EM and magic angle spinning NMR measurements to determine the structure of a β2m fibril and they also present the low resolution model of a β2m fibril with a different morphology.

Article | Open Access | | Nature Communications

Amyloid fibril structures can display polymorphism. Here the authors reveal the cryo-EM structures of several different fibril morphologies of a peptide derived from an amyloidogenic immunoglobulin light chain and present a mathematical analysis of physical factors that influence fibril polymorphism.

Article | Open Access | | Nature Communications

Prion diseases can be transmitted across species. Here the authors use solid-state NMR to study prion protein (PrP) amyloids from human, mouse and Syrian hamster and show that their structural differences are mainly governed by two residues, which helps to understand interspecies PrP propagation on a molecular level.

Article | Open Access | | Nature Communications

Huntington's disease is caused by a polyglutamine stretch expansion in the first exon of huntingtin. Here, the authors use infrared spectroscopy and solid-state NMR and show that polymorphic huntingtin exon1 fibres differ in their flanking regions but not their core polyglutamine amyloid structures.

Article | Open Access | | Nature Communications

Parkinson’s disease (PD) and Multiple System Atrophy (MSA) are characterized by the pathological accumulation of α-synuclein. Here the authors employ fluorescent probes, electron microscopy and NMR spectroscopy to study the properties of α-synuclein aggregates that were amplified from patient brain extracts and observe a greater structural diversity among PD patients compared to MSA patients.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

G51D mutation of α-synuclein (α-syn) causes a subset of familial Parkinson’s disease that is characterized by an early onset and rapid progression of the disease. Here, the authors present the cryo-EM structure of full-length G51D α-syn fibrils that is distinct from other known α-syn fibril structures, and they show that G51D fibrils can cross-seed wild-type (WT) α-syn and that these cross-seeded WT fibrils replicate the G51D fibril structure.

Article | Open Access | | Nature Communications

Functional amyloids

The phenol-soluble modulin PSMα3 secreted by Staphylococcus aureus forms cross-α amyloid-like fibrils. Here the authors reveal the amyloid polymorphism of PSMs by presenting the cross-β amyloid fibril structures of the biofilm-associated PSMα1 and PSMα4 and showing that truncated PSMα3 antibacterial peptides form distinct out-of-register β-sheets and a polymorph with a hexameric architecture of β-sheets.

Article | Open Access | | Nature Communications

The human antibacterial and immunomodulatory peptide LL-37 is a hCAP-18 protein cleavage product that self-assembles. Here, the authors present the human and gorilla LL-37 (17–29) crystal structures, revealing a self-assembly of amphipathic helices into a densely packed and elongated hexameric structure with a central pore and mutagenesis experiments support the role of self-assembly for antibacterial activity.

Article | Open Access | | Nature Communications