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Woods LA Platt GW Hellewell AL Hewitt EW Homans SW Ashcroft AE Radford SE 《Nature chemical biology》2011,7(10):730-739
Although small molecules that modulate amyloid formation in vitro have been identified, significant challenges remain in determining precisely how these species act. Here we describe the identification of rifamycin SV as a potent inhibitor of β(2) microglobulin (β(2)m) fibrillogenesis when added during the lag time of assembly or early during fibril elongation. Biochemical experiments demonstrate that the small molecule does not act by a colloidal mechanism. Exploiting the ability of electrospray ionization-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS) to resolve intermediates of amyloid assembly, we show instead that rifamycin SV inhibits β(2)m fibrillation by binding distinct monomeric conformers, disfavoring oligomer formation and diverting the course of assembly to the formation of spherical aggregates. The results demonstrate the power of ESI-IMS-MS to identify specific protein conformers as targets for intervention in fibrillogenesis using small molecules and reveal a mechanism of action in which ligand binding diverts unfolded protein monomers toward alternative assembly pathways. 相似文献
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Seahorses (Hippocampus spp.) are non-sex-role-reversed members of the Syngnathidae family that provide extensive brood care. Previous studies of
seahorses have revealed monogamy within a single brood, but their longer term mating system had not been comprehensively evaluated.
The parental contribution to 29 wild-born broods of Hippocampus guttulatus, sampled from six Portuguese populations with differing seahorse densities and sex ratios, was assessed using microsatellite
DNA markers. To assess the longer term genetic mating system of this species parentage was determined in eleven broods sampled
from a captive population over two breeding seasons. Genetic data suggest that this socially polygamous seahorse is serially
monogamous across breeding seasons, i.e. monogamous within a season but may switch mates between seasons, and that differing
population densities and sex ratios do not affect the mating system. 相似文献
158.
Fairfield H Gilbert GJ Barter M Corrigan RR Curtain M Ding Y D'Ascenzo M Gerhardt DJ He C Huang W Richmond T Rowe L Probst FJ Bergstrom DE Murray SA Bult C Richardson J Kile BT Gut I Hager J Sigurdsson S Mauceli E Di Palma F Lindblad-Toh K Cunningham ML Cox TC Justice MJ Spector MS Lowe SW Albert T Donahue LR Jeddeloh J Shendure J Reinholdt LG 《Genome biology》2011,12(9):R86-12
We report the development and optimization of reagents for in-solution, hybridization-based capture of the mouse exome. By validating this approach in a multiple inbred strains and in novel mutant strains, we show that whole exome sequencing is a robust approach for discovery of putative mutations, irrespective of strain background. We found strong candidate mutations for the majority of mutant exomes sequenced, including new models of orofacial clefting, urogenital dysmorphology, kyphosis and autoimmune hepatitis. 相似文献
159.
The osmoregulated betaine transporter BetP is a stable trimer. Structural studies have shown that individual protomers can adopt distinct transport conformations, implying a functional role for the trimeric state in transport, although the role of trimerization in regulation is not yet understood. We designed putative monomeric mutants by molecular-dynamics simulations and in silico alanine-scanning mutagenesis. Several mutants including BetP-W101A/T351A were monomeric in detergent as well as in the membrane, as shown by blue native gel electrophoresis, crosslinking and electron microscopy. This monomeric form retains the ability to accumulate betaine, but is no longer regulated by hyperosmotic shock. 相似文献
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