@article {64833, title = {Cryo-EM fibril structures from systemic AA amyloidosis reveal the species complementarity of pathological amyloids.}, journal = {Nature Communications}, volume = {10}, year = {2019}, month = {2019 Mar 07}, pages = {1104}, abstract = {

Systemic AA amyloidosis is a worldwide occurring protein misfolding disease of humans and animals. It arises from the formation of amyloid fibrils from the acute phase protein serum amyloid A. Here, we report the purification and electron cryo-microscopy analysis of amyloid fibrils from a mouse and a human patient with systemic AA amyloidosis. The obtained resolutions are 3.0 {\r A} and 2.7 {\r A} for the murine and human fibril, respectively. The two fibrils differ in fundamental properties, such as presence of right-hand or left-hand twisted cross-β sheets and overall fold of the fibril proteins. Yet, both proteins adopt highly similar β-arch conformations within the N-terminal ~21 residues. Our data demonstrate the importance of the fibril protein N-terminus for the stability of the analyzed amyloid fibril morphologies and suggest strategies of combating this disease by interfering with specific fibril polymorphs.

}, issn = {2041-1723}, doi = {10.1038/s41467-019-09033-z}, author = {Liberta, Falk and Loerch, Sarah and Rennegarbe, Matthies and Schierhorn, Angelika and Westermark, Per and Westermark, Gunilla T and Hazenberg, Bouke P C and Grigorieff, Nikolaus and F{\"a}ndrich, Marcus and Schmidt, Matthias} } @article {49049, title = {Physical basis of amyloid fibril polymorphism.}, journal = {Nature Communications}, volume = {9}, year = {2018}, month = {2018 Feb 16}, pages = {699}, abstract = {

Polymorphism is a key feature of amyloid fibril structures but it remains challenging to explain these variations for a particular sample. Here, we report electron cryomicroscopy-based reconstructions from different fibril morphologies formed by a peptide fragment from an amyloidogenic immunoglobulin light chain. The observed fibril morphologies vary in the number and cross-sectional arrangement of a structurally conserved building block. A comparison with the theoretically possible constellations reveals the experimentally observed spectrum of fibril morphologies to be governed by opposing sets of forces that primarily arise from the β-sheet twist, as well as peptide-peptide interactions within the fibril cross-section. Our results provide a framework for rationalizing and predicting the structure and polymorphism of cross-β fibrils, and suggest that a small number of physical parameters control the observed fibril architectures.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-03164-5}, author = {Close, William and Neumann, Matthias and Schmidt, Andreas and Hora, Manuel and Annamalai, Karthikeyan and Schmidt, Matthias and Reif, Bernd and Schmidt, Volker and Grigorieff, Nikolaus and F{\"a}ndrich, Marcus} } @article {47506, title = {Cryo-EM reveals the steric zipper structure of a light chain-derived amyloid fibril.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {113}, year = {2016}, month = {2016 May 16}, pages = {6200-5}, abstract = {

Amyloid fibrils are proteinaceous aggregates associated with diseases in humans and animals. The fibrils are defined by intermolecular interactions between the fibril-forming polypeptide chains, but it has so far remained difficult to reveal the assembly of the peptide subunits in a full-scale fibril. Using electron cryomicroscopy (cryo-EM), we present a reconstruction of a fibril formed from the pathogenic core of an amyloidogenic immunoglobulin (Ig) light chain. The fibril density shows a lattice-like assembly of face-to-face packed peptide dimers that corresponds to the structure of steric zippers in peptide crystals. Interpretation of the density map with a molecular model enabled us to identify the intermolecular interactions between the peptides and rationalize the hierarchical structure of the fibril based on simple chemical principles.

}, issn = {1091-6490}, doi = {10.1073/pnas.1522282113}, author = {Schmidt, Andreas and Annamalai, Karthikeyan and Schmidt, Matthias and Grigorieff, Nikolaus and F{\"a}ndrich, Marcus} } @article {48313, title = {Peptide dimer structure in an Aβ(1-42) fibril visualized with cryo-EM.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {112}, year = {2015}, month = {2015 Sep 22}, pages = {11858-63}, abstract = {

Alzheimer{\textquoteright}s disease (AD) is a fatal neurodegenerative disorder in humans and the main cause of dementia in aging societies. The disease is characterized by the aberrant formation of β-amyloid (Aβ) peptide oligomers and fibrils. These structures may damage the brain and give rise to cerebral amyloid angiopathy, neuronal dysfunction, and cellular toxicity. Although the connection between AD and Aβ fibrillation is extensively documented, much is still unknown about the formation of these Aβ aggregates and their structures at the molecular level. Here, we combined electron cryomicroscopy, 3D reconstruction, and integrative structural modeling methods to determine the molecular architecture of a fibril formed by Aβ(1-42), a particularly pathogenic variant of Aβ peptide. Our model reveals that the individual layers of the Aβ fibril are formed by peptide dimers with face-to-face packing. The two peptides forming the dimer possess identical tilde-shaped conformations and interact with each other by packing of their hydrophobic C-terminal β-strands. The peptide C termini are located close to the main fibril axis, where they produce a hydrophobic core and are surrounded by the structurally more flexible and charged segments of the peptide N termini. The observed molecular architecture is compatible with the general chemical properties of Aβ peptide and provides a structural basis for various biological observations that illuminate the molecular underpinnings of AD. Moreover, the structure provides direct evidence for a steric zipper within a fibril formed by full-length Aβ peptide.

}, keywords = {Amino Acid Sequence, Amyloid, Amyloid beta-Peptides, Cryoelectron Microscopy, Epitope Mapping, Image Processing, Computer-Assisted, Immunoglobulin Fab Fragments, Models, Molecular, Molecular Sequence Data, Peptide Fragments, Peptides, Protein Multimerization, Protein Structure, Secondary}, issn = {1091-6490}, doi = {10.1073/pnas.1503455112}, author = {Schmidt, Matthias and Rohou, Alexis and Lasker, Keren and Yadav, Jay K and Schiene-Fischer, Cordelia and F{\"a}ndrich, Marcus and Grigorieff, Nikolaus} } @article {6333, title = {Recent progress in understanding Alzheimer{\textquoteright}s β-amyloid structures.}, journal = {Trends in Biochemical Sciences}, volume = {36}, year = {2011}, month = {2011 Jun}, pages = {338-45}, abstract = {

The formation of amyloid fibrils, protofibrils and oligomers from the β-amyloid (Aβ) peptide represents a hallmark of Alzheimer{\textquoteright}s disease. Aβ-peptide-derived assemblies might be crucial for disease onset, but determining their atomic structures has proven to be a major challenge. Progress over the past 5 years has yielded substantial new data obtained with improved methodologies including electron cryo-microscopy and NMR. It is now possible to resolve the global fibril topology and the cross-β sheet organization within protofilaments, and to identify residues that are crucial for stabilizing secondary structural elements and peptide conformations within specific assemblies. These data have significantly enhanced our understanding of the mechanism of Aβ aggregation and have illuminated the possible relevance of specific conformers for neurodegenerative pathologies.

}, keywords = {Alzheimer Disease, Amyloid, Amyloid beta-Peptides, Animals, Humans, Protein Conformation}, issn = {0968-0004}, doi = {10.1016/j.tibs.2011.02.002}, author = {F{\"a}ndrich, Marcus and Schmidt, Matthias and Grigorieff, Nikolaus} }