RESEARCH - Daniel Kümmel


and Structural biology


Molecular function of the TSC tumor suppressor complex


The TOR (target of rapamycin) kinase complex 1 (mTORC1) 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 mTORC1 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 mechanisms underlying TSC complex function and regulation, and the molecular basis of tuberous sclerosis pathogenesis are poorly understood. To provide novel insight and elucidate these aspects, we work on the structural and biochemical characterization of the TSC complex.

Fitzian et. al (2021)
TSC1 binding to lysosomal PIPs is required for TSC complex translocation and mTORC1 regulation.
Mol Cell doi: 10.1016/j.molcel.2021.04.019

Hansmann et al (2020)
Structure of the TSC2 GAP Domain: Mechanistic Insight into Catalysis and Pathogenic Mutations.
Structure doi: 10.1016/j.str.2020.05.008

Zech et al (2016)
Structure of the Tuberous Sclerosis Complex 2 (TSC2) N Terminus Provides Insight into Complex
Assembly and Tuberous Sclerosis Pathogenesis. J Biol Chem doi: 10.1074/jbc.M116.732446