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Giller, K.

Publications and source records attributed to Giller, K..

2 recordsLinked to original sources
bioRxiv2023

Cryo-EM structures of lipidic fibrils of amyloid-β (1-40)

Alzheimers disease (AD) is a progressive and incurable neurodegenerative disease characterized by the extracellular deposition of amyloid plaques. Investigation into the composition of these plaques revealed a high amount of amyloid-{beta} (A{beta}) fibrils and a high concentration of lipids, suggesting that fibril-lipid interactions may also be relevant for the pathogenesis of AD. Therefore, we grew A{beta}40 fibrils in the presence of lipid vesicles and determined their structure by cryo-electron microscopy (cryo-EM) to high resolution. The fold of the major polymorph is similar to the structure of brain-seeded fibrils reported previously. The majority of the lipids are bound to the fibrils as we show by cryo-EM and NMR spectroscopy. This apparent lipid extraction from vesicles observed here in vitro provides structural insights into potentially disease-relevant fibril-lipid interactions.

molecular biology↗
bioRxiv2023

Mechanism of sensor kinase CitA transmembrane signaling

Membrane bound histidine kinases (HKs) are ubiquitous sensors of extracellular stimuli in bacteria. Here, we used solid-state NMR in conjunction with crystallography, solution NMR and distance measurements to investigate the transmembrane signaling mechanism of a paradigmatic citrate sensing membrane embedded HK, CitA. Citrate binding in the sensory extracytoplasmic PAS domain (PASp) causes the linker to transmembrane helix 2 (TM2) to adopt a helical conformation. This triggers a piston-like pulling of TM2 and a quaternary structure rearrangement in the cytosolic PAS domain (PASc). Crystal structures of PASc reveal both anti-parallel and parallel dimer conformations. An anti-parallel to parallel transition upon citrate binding agrees with interdimer distances measured in the lipid embedded protein using a site-specific 19F label in PASc. These data show how Angstrom scale structural changes in the sensor domain are transmitted across the membrane to be converted and amplified into a nm scale shift in the linker to the phosphorylation subdomain of the kinase. One-Sentence SummaryTransmembrane signal transduction of a PAS-domain containing histidine kinase occurs via a piston-like pulling of a transmembrane helix, and amplification by cytoplasmic PAS domain dimer rearrangement.

molecular biology↗