Dynamic structure of lipid-bound synaptobrevin suggests a nucleation-propagation mechanism for trans-SNARE complex formation

The synaptic vesicle protein synaptobrevin engages with syntaxin and SNAP-25 to form the SNARE complex, which drives membrane fusion in neuronal exocytosis. In the SNARE complex, the SNARE motif of synaptobrevin forms a 55-residue helix, but it has been assumed to be mostly unstructured in its prefusion form. NMR data for full-length synaptobrevin in dodecylphosphocholine micelles reveals two transient helical segments flanked by natively disordered regions and a third more stable helix. Transient helix I comprises the most N-terminal part of the SNARE motif, transient helix II extends the SNARE motif into the juxtamembrane region, and the more stable helix III is the transmembrane domain. These helices may have important consequences for SNARE complex folding and fusion: helix I likely forms a nucleation site, the C-terminal disordered SNARE motif may act as a folding arrest signal, and helix II likely couples SNARE complex folding and fusion.     

Cytotoxic activity in the serum of a patient with metastasizing nephroblastoma given intravenous infusions of alkyl-lysophospholipids in a phase I study

Summary In a phase I study a cytotoxic activity in the serum of a tumor patient given infusions of synthetic alkyl-lysophospholipid has been demonstrated. Serum samples collected after ALP infusions inhibited ³H-thymidine incorporation by human leukemic cells to an extent that correlated to the dose of ALP administered. Serum taken after the highest dose of ALP given (50 mg/kg body weight) led to complete cell destruction after 72 h in vitro. Whereas cells from the HL60 line were very sensitive to the serum cytotoxicity, K562 cells were much less affected. Cytotoxic activity was found to be cleared from the circulation in a biphasic manner; more than 50% disappeared within 6–8 h but 20–30% was still present after 4 days.Supported by DFG An 111/2