The formation of oligomers of the amyloid-β peptide plays a key role in the onset of Alzheimer's disease. We describe herein the investigation of disease-relevant small amyloid-β oligomers by mass spectrometry and ion mobility spectrometry, revealing functionally relevant structural attributes. In particular we can show that amyloid-β oligomers develop in two distinct arrangements leading to either neurotoxic oligomers and fibrils or non-toxic amorphous aggregates. Comprehending the key-attributes responsible for those pathways on a molecular level is a pre-requisite to specifically target the peptide's tertiary structure with the aim to promote the emergence of non-toxic aggregates. Here we show for two fibril inhibiting ligands, an ionic molecular tweezer and a hydrophobic peptide that despite their different interaction mechanisms, the suppression of the fibril pathway can be deduced from the disappearance of the corresponding structure of the first amyloid-β oligomers.
Conjugation in the anther smut fungus, Ustilago violacea, is described and five stages are characterized viz. (i) intimate pairing of cells of opposite mating type; (ii) development of bumps from each cell at the point of pairing. The cell walls of opposing pegs are fused, but the plasma membranes are not yet affected; (iii) elongation of the bumps into pegs; (iv) dissolution of the walls and plasma membranes of opposing pegs at the point of contact, and the formation of a tube; (v) elongation of the tube to the mature mating configuration (about 5 μm). Electron micrographs and Nomarski interference contrast micrographs of this sequence are illustrated. The assembly of the conjugation tube begins as early as 1.5 h after the cells are mixed on mating medium and is completed in about 45 min. Even in asynchronous populations there is a burst of synchronous mating, followed by later asynchronous mating. Observations on the ability to mate of unbudded and budded cells support the evidence from cell cycle work that allele a1 mates only in the G1 phase (unbudded) while allele a2 is competent to mate during all phases.
The TOM complex is the main entry point for precursor proteins (preproteins) into mitochondria. Preproteins containing targeting sequences are recognized by the TOM complex and imported into mitochondria. We have determined the structure of the TOM core complex from
Neurospora crassa
by single-particle electron cryomicroscopy at 3.3 Å resolution, showing its interaction with a bound preprotein at 4 Å resolution, and of the TOM holo complex including the Tom20 receptor at 6 to 7 Å resolution. TOM is a transmembrane complex consisting of two β-barrels, three receptor subunits, and three short transmembrane subunits. Tom20 has a transmembrane helix and a receptor domain on the cytoplasmic side. We propose that Tom20 acts as a dynamic gatekeeper, guiding preproteins into the pores of the TOM complex. We analyze the interactions of Tom20 with other TOM subunits, present insights into the structure of the TOM holo complex, and suggest a translocation mechanism.
The TOM complex is the main entry point for precursor proteins into mitochondria. Precursor proteins containing targeting sequences are recognized by the TOM complex and imported into the mitochondria. We have determined the structure of the TOM core complex from Neurospora crassa by single-particle cryoEM at 3.3 Angstrom resolution, showing its interaction with a bound presequence at 4 Angstrom resolution, and of the TOM holo complex including the Tom20 receptor at 6-7 Angstrom resolution. TOM is a transmembrane complex consisting of two beta-barrels, three receptor subunits and three short transmembrane subunits. Tom20 has a transmembrane helix and a receptor domain on the cytoplasmic side. We propose that Tom20 acts as a dynamic gatekeeper, guiding precursor proteins into the pores of the TOM complex. We analyze the interactions of Tom20 with other TOM subunits, present insights into the structure of the TOM holo complex, and suggest a translocation mechanism.
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