Exploring Arylidene-Indolinone Ligands of Autophagy Proteins LC3B and GABARAP.

We report the first structure-activity studies of arylidene-indolinone compound which was reported as a ligand of autophagy-related protein LC3B. The literature has conflicting information on the binding affinity of this compound and there is some debate regarding its use as a component of autophagy-dependent degrader compounds. We developed an AlphaScreen assay to measure competitive inhibition of the binding of known peptide ligands to LC3B and its paralog GABARAP.

Atomic Resolution Insights into pH Shift Induced Deprotonation Events in LS-Shaped Aβ(1-42) Amyloid Fibrils.

Alzheimer's disease is a neurodegenerative disorder associated with the deposition of misfolded aggregates of the amyloid-β protein (Aβ). Aβ(1-42) is one of the most aggregation-prone components in senile plaques of AD patients. We demonstrated that relatively homogeneous Aβ(1-42) fibrils with one predominant fold visible in solid-state NMR spectra can be obtained at acidic pH.

Structural details of amyloid β oligomers in complex with human prion protein as revealed by solid-state MAS NMR spectroscopy.

Human PrP (huPrP) is a high-affinity receptor for oligomeric amyloid β (Aβ) protein aggregates. Binding of Aβ oligomers to membrane-anchored huPrP has been suggested to trigger neurotoxic cell signaling in Alzheimer's disease, while an N-terminal soluble fragment of huPrP can sequester Aβ oligomers and reduce their toxicity. Synthetic oligomeric Aβ species are known to be heterogeneous, dynamic, and transient, rendering their structural investigation particularly challenging.

Clustering of human prion protein and α-synuclein oligomers requires the prion protein N-terminus.

The interaction of prion protein (PrP) and α-synuclein (αSyn) oligomers causes synaptic impairment that might trigger Parkinson's disease and other synucleinopathies. Here, we report that αSyn oligomers (αSynO) cluster with human PrP (huPrP) into micron-sized condensates. Multivalency of αSyn within oligomers is required for condensation, since clustering with huPrP is not observed for monomeric αSyn.

TopModel: Template-Based Protein Structure Prediction at Low Sequence Identity Using Top-Down Consensus and Deep Neural Networks.

Knowledge of protein structures is essential to understand proteins' functions, evolution, dynamics, stabilities, and interactions and for data-driven protein- or drug design. Yet, experimental structure determination rates are far exceeded by that of next-generation sequencing, resulting in less than 1/1000th of proteins having an experimentally known 3D structure. Computational structure prediction seeks to alleviate this problem, and the Critical Assessment of Protein Structure Prediction (CASP) has shown the value of consensus and meta-methods that utilize complementary algorithms.