Biology subjects

Schroeder, G. F.

Publications and source records attributed to Schroeder, G. F..

6 recordsLinked to original sources

bioRxiv2025

Lecanemab binds to transgenic mouse model-derived amyloid-β fibril structures resembling Alzheimer 's disease type-I, type-II and Arctic folds

Lecanemab, an Alzheimers disease US Food and Drug Administration approved monoclonal antibody was previously reported to have a high affinity against intermediately sized amyloid-{beta} aggregates. Subsequently, it was observed by immunogold labelling that lecanemab can also bind to human type-I amyloid-{beta} fibrils. Therefore, to determine whether lecanemab binds to amyloid-{beta} fibril structures other than type-I, we performed immunogold labelling on extracted amyloid-{beta} fibril preparations from six different Alzheimers disease mouse models whose structures were previously solved by cryo-EM. Our results show that lecanemab exhibits high binding affinity to amyloid-{beta} fibril structures that have a flexible N-terminus in common, as it is the case for type-I, type-II and murine type-III amyloid-{beta} fibril polymorphs which resemble or are identical to human structures observed in sporadic and familial cases of Alzheimers disease, including a case with the Arctic (E22G) mutation. In contrast, only weak, if any, lecanemab binding was observed for amyloid-{beta} fibril folds with a fixed and ordered N-terminus. Key points- Lecanemab binds to A{beta} fibrils from several Alzheimers disease tg-mice whose structures resemble the type-I, type-II and Arctic folds found in Alzheimers patients, all of which share a flexible, unstructured N-terminus. - Lecanemab is therefore expected to be active against all common familial and sporadic Alzheimers cases containing these folds. - Lecanemab binding ability is unaffected by and tolerates the Arctic E22G mutation, at least in type-I or Arctic folds. - Weak, if any, lecanemab binding was observed to A{beta} fibrils derived from tg-SwDI mice, whose structures DI1, DI2 and DI3 all share structured and fixed N-termini. - Since the fixed N-termini of tg-SwDI DI1 fibrils and human meningeal A{beta}40 fibrils derived from CAA-affected brain are identical, most likely preventing lecanemab binding, treatment with lecanemab may be less or ineffective against CAA, but may explain the reported beneficial low ARIA-E frequency with this antibody. Table of Contents Graphic (TOC) O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/633637v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@b1e636org.highwire.dtl.DTLVardef@180efe4org.highwire.dtl.DTLVardef@58668org.highwire.dtl.DTLVardef@bb481e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Capturing G protein-coupled receptors into native lipid-bilayer nanodiscs using new diisobutylene/maleic acid (DIBMA) copolymers

Many membrane proteins, including G-protein-coupled receptors (GPCRs), are susceptible to denaturation when extracted from their native membrane by detergents. Therefore, alternative methods have been developed, including amphiphilic copolymers that enable the direct extraction of functional membrane proteins along with their surrounding lipids, leading to the formation of native lipid-bilayer nanodiscs. Among these amphiphilic copolymers, styrene/maleic acid (SMA) and diisobutylene/maleic acid (DIBMA) polymers have been extensively studied and successfully utilized to isolate various types of membrane proteins, including GPCRs. Despite their many benefits, SMA and DIBMA polymers also have significant drawbacks that limit their application. Most notably, both SMA and DIBMA carry high negative charge densities, which can interfere with protein-protein and protein-lipid interactions through unspecific Coulombic attraction or repulsion. Herein, we describe a series of new amphiphilic copolymers derived from DIBMA via partial amidation of the carboxylate pendant groups with various biocompatible amines. The nanodisc-forming properties of the new polymers were assessed using model membranes as well as in the context of extracting the melanocortin 4 receptor (MC4R), a prototypical class A GPCR. While each new DIBMA variant displays distinct features that may be favorable for selected applications, we identified a new PEGylated DIBMA variant called mPEG4-DIBMA as particularly promising for the studied purpose. On the one hand, mPEG4-DIBMA abolishes unspecific interactions with the tested peptide ligand, a prerequisite for reliably characterizing GPCR-ligand interactions. On the other hand, mPEG4-DIBMA outperforms other polymers such as SMA and DIBMA by achieving higher extraction efficiencies of MC4R from Sf9 insect cell membranes. Thus, this new nanodisc-forming polymer combines two key advantages that are crucial for investigating GPCRs in a well-defined but still native lipid-bilayer environment, thus paving the way for manifold future applications.

biochemistry↗

bioRxiv2021

α-Synuclein polymorphism determines oligodendroglial dysfunction

Synucleinopathies, such as Parkinsons disease (PD) and Multiple System Atrophy (MSA) are progressive and unremitting neurological diseases. For both PD and MSA, -synuclein fibril inclusions inside brain cells are neuropathological hallmarks. In addition, amplification of -synuclein fibrils from body fluids is a potential biomarker distinguishing PD from MSA. However, little is known about the structure of -synuclein fibrils amplified from human samples and its connection to -synuclein fibril structure in the human brain. Here we amplified -synuclein fibrils from PD and MSA brain tissue, characterized its seeding potential in oligodendroglia, and determined the 3D structures by cryo-electron microscopy. We show that the -synuclein fibrils from a MSA patient are more potent in recruiting the endogenous -synuclein and evoking a redistribution of TPPP/p25 protein in mouse primary oligoden-droglial cultures compared to those amplified from a PD patient. Cryo-electron microscopy shows that the PD- and MSA-amplified -synuclein fibrils share a similar protofilament fold but differ in their inter-protofilament interface. The structures of the brain-tissue amplified -synuclein fibrils are also similar to other in vitro and ex vivo -synuclein fibrils. Together with published data, our results suggest that Syn fibrils differ between PD and MSA in their quaternary arrangement and could further vary between different forms of PD and MSA.

neuroscience↗

bioRxiv2020

Spinal Column Architecture of the Flexible SPP1 Bacteriophage Tail Tube

Phage therapy has recently regained attention at combating multidrug-resistant bacteria. In 2019, tailed bacteriophages of the Siphoviridae family were engineered to successfully treat a disseminated bacterial infection after all other drugs had failed.(1) This family of phages features a long, flexible, non-contractile tail that has been difficult to characterize structurally. Here, we present the atomic structure of the tail-tube of the bacteriophage SPP1 - a member of this family. Our hybrid structure is based on the integration of structural restraints from solid-state NMR and a density map from cryo-EM. We show that the tail tube protein (TTP) gp17.1 organizes into hexameric rings that are stacked by flexible linker domains and, thus, form a hollow flexible tube with a negatively charged lumen suitable for the transport of DNA. One sentence summaryIntegrative structural biology by solid-state NMR and cryo-EM enables structure determination of the flexible tail of the bacteriophage SPP1.

biophysics↗

bioRxiv2020

Outcomes of the 2019 EMDataResource model challenge: validation of cryo-EM models at near-atomic resolution

This paper describes outcomes of the 2019 Cryo-EM Map-based Model Metrics Challenge sponsored by EMDataResource (www.emdataresource.org). The goals of this challenge were (1) to assess the quality of models that can be produced using current modeling software, (2) to check the reproducibility of modeling results from different software developers and users, and (3) compare the performance of current metrics used for evaluation of models. The focus was on near-atomic resolution maps with an innovative twist: three of four target maps formed a resolution series (1.8 to 3.1 [A]) from the same specimen and imaging experiment. Tools developed in previous challenges were expanded for managing, visualizing and analyzing the 63 submitted coordinate models, and several novel metrics were introduced. The results permit specific recommendations to be made about validating near-atomic cryo-EM structures both in the context of individual laboratory experiments and holdings of structure data archives such as the Protein Data Bank. Our findings demonstrate the relatively high accuracy and reproducibility of cryo-EM models derived from these benchmark maps by 13 participating teams, representing both widely used and novel modeling approaches. We also evaluate the pros and cons of the commonly used metrics to assess model quality and recommend the adoption of multiple scoring parameters to provide full and objective annotation and assessment of the model, reflective of the observed density in the cryo-EM map.

biochemistry↗

bioRxiv2020

Amyloid fibril structure of islet amyloid polypeptide by cryo-electron microscopy reveals similarities with amyloid beta

A critical role of the hormone islet amyloid polypeptide (IAPP) is vividly discussed for Type 2 Diabetes (T2D), where amyloid deposits in pancreatic islets consisting of fibrillar IAPP have been associated with beta cell loss. Here, we applied cryo-electron microscopy to elucidate the structure of IAPP fibrils prepared at physiological pH and reconstructed densities of three dominant polymorphs. An atomic model of the main polymorph comprising residues 13 - 37 in a density map of 4.2 [A] resolution reveals two S-shaped, intertwined protofilaments. The segment 21-NNFGAIL-27, which is essential for IAPP amyloidogenicity, forms the protofilament interface together with tyrosine 37 and the amidated C-terminus. The main IAPP fibril polymorph resembles polymorphs of the Alzheimer disease (AD)-associated amyloid-{beta} peptide (A{beta}), which is striking in light of the epidemiological link between T2D and AD and reports on IAPP-A{beta} cross-seeding in vivo. The results structurally link the early-onset T2D IAPP genetic polymorphism S20G with the early-onset AD Arctic mutation E22G of A{beta}, rationalize previous data on IAPP fibrils, help to elucidate mechanisms of amyloid formation and toxicity, and support the design of fibril growth inhibitors as well as imaging probes for early detection of IAPP fibrils.

biochemistry↗