Our research aims to reveal the mechanisms and machinery underlying intracellular vesicle targeting and regulated membrane fusion. Regulated exocytosis plays a key role in short- and long-range communication and allows complex organisms to react appropriately to various stimuli by releasing mediators, such as hormones, growth factors, and neurotransmitters in a temporally and spatially controlled manner.
We are taking 2 avenues to accomplish our research goals. One is intended to isolate new components, followed by a functional analysis in an environment close to intact cells. The other shall reveal the detailed molecular mechanisms of how distinct components fulfill their functions by making use of a completely reconstituted assay employing SNARE-mediated fusion as an analysis platform. The primary model system for all of these studies is the neuronal synapse, which (like other membrane fusion) steps employs a basic targeting and fusion machinery, but in addition is characterized by its localized vesicle docking and precise regulation. The long-term goal is to reconstitute the sequential series of molecular events, starting with synaptic vesicle recruitment and docking to the active zone, followed by various steps priming the machinery and finally resulting in Ca2+ triggered fusion.
To explore the exact molecular mechanisms by which individual components or functional protein assemblies regulate vesicle fusion, we make use of our previous observation that SNAREs are the minimal machinery for membrane fusion. SNARE proteins, a family of compartmentally specific integral membrane proteins, spontaneously fuse lipid bilayers when reconstituted into liposomes. Addition of regulatory components will affect the fusion kinetics and probability. Basic machinery presently under analysis includes tethering proteins, Rab proteins and their effectors, Sec1/Munc18 proteins, and calcium-sensors. The potentially superimposed fine-tuning underlying synapse modulation during adaptive processes, such as synaptic facilitation and repression, will become another subject of investigation.
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