Philipp Lachenmann: DELPHI Rationale


Habilitationspreis 2004

PD Dr. Christian Ungermann

Biochemie Zentrum der Universität Heidelberg

Regulation and dynamics of membrane fusion: function of SNARE proteins during fusion of yeast vacuoles

Eukarotic cells contain multiple compartments/organelles of specific protein and lipid composition. Within the endomembrane system, the maintenance of organelle identity becomes a challenge, since transport of proteins and lipids between organelles occurs by vesicular transport: vesicles bud off from one compartment (e.g. the Endoplasmic reticulum) and fuse with the next (the Golgi).

Vesicle budding requires coat proteins that allow deformation of the membrane. For fusion, it has become clear that a conserved set of proteins is required: Rab-GTPases, that interact with tethering factors, proteins of the SNARE family that localized to vesicles and organelles of the endomembrane system and form defined complexes when membranes meet, and NSF (in yeast Sec18), a AAA-ATPase that activates/recycles the machinery. Our main interest is membrane fusion and organelle dynamics.

Yeast vacuoles are an ideal model system to monitor intracellular organelle dynamics. Vacuoles are large single copy organelles, corresponding to the mammalian lysosome. In response to changes in the cellular osmolarity or during cell division vacuoles undergo dramatic morphological changes and fragment. Likewise, vacuoles fuse to regain their original size. Like other intracellular fusion events, vacuoles fusion depends on previously described fusion machinery.

Initially, we identified a number of factors involved in the vacuole fusion reaction, including five SNARE proteins, and could show their role in the fusion reaction. Our work provided evidence that membrane fusion follows an ordered cascade of activation of protein complexes on vacuoles, followed by SNARE-dependent membrane docking and fusion of lipid bilayers. With the establishment of a basic reaction cascade, we began to characterize two regulatory events: a revesible lipid modification of proteins, termed palmitoylation, and protein phosphorylation.

My group could identify an essential fusion factor (Vac8) that becomes palmitoylated during the fusion reaction. Our data indicate that one SNARE (Ykt6) mediates the palmitoylation of Vac8 in a novel reaction on yeast vacuoles. The role of the conserved Ykt6 protein, which is also lipid modified, is a present focus of the lab. Future interests are the precise mechanism of protein palmitoylation on yeast vacuoles and its regulation. Additional work will deal with vacuole dynamics in vivo and proteins that control this process by phosphorylation.



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