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RESEARCH - D. Kümmel - Biochemistry / Structural biology

Regulation of small GTPases in the endolysosomal system  
 

Maintenance of cellular homeostasis requires the transport of substances between different compartments of the cell and its exterior as well as the coordination with growth signaling pathways. In this context, the lysosome (vacuole in yeast) is a central organell: as the endpoint of several trafficking pathways and the central recycling station of the cell, it senses the nutritional status of the cell and conveys this information to regulate cell growth. We are interested in the regulation of trafficking and signaling at the lysosome, how these processes are linked and how they can contribute to diseases like cancer.

We focus on the regulation small GTPases, which are molecular switches that cycle between an inactive and an active state. Their function requires activator (guanine nucleotide exchange factors, GEFs) and inactivator (GTPase activating proteins, GAPs) proteins that are responsible f or the conversion between the on and off states.

The Mon1-Ccz1 complex in vesicular traffic

Extracellular substances and cell surface proteins are internalized by endocytic vesicles, which fuse to form early endosome. These organelles are positive for the marker GTPase Rab5 and here cargo is sorted and recycled. Alternatively, the content is delivered to the lysosome for degradation, which requires the maturation into a late endosome through the conversion into a Rab7-positive membrane. The molecular mechanism of this process is poorly understood, but the Mon1-Ccz1 (MC1) complex has been identified as a key player: MC1 is recruited by Rab5 and acts as GEF (activator) for Rab7 and thus initiates organelle conversion. We study the structure and function of MC1 to gain better insight into the mechanism and regulation of endosomal maturation.

The TSC complex regulates growth signaling

The TOR (target of rapamycin) kinase complex is a master regulator of cellular growth and requires, among other inputs, growth factor signaling for its full activation. This signal is conveyed by the Rheb GTPase: under resting conditions, Rheb is kept inactive by its GAP (inactivator) called TSC (tuberous sclerosis) complex. When growth factors are present, the TSC complex is switch off, thus Rheb and TORC become active. Importantly, mutations in the TSC complex cause the genetic disease tuberous sclerosis, which is characterized by the formation of benign tumors in skin, heart, lung and the brain, which lead to organ failure. The mechanism of Rheb regulation by the TSC complex and the molecular basis of tuberous sclerosis pathogenesis are poorly understood. We hope to elucidate these aspects by the structural and biochemical characterization of the TSC complex.


 

Group members

General publication list

D. Kümmel:  CV   Contact



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