Proteus Syndrome is named after a sea deity from Greek mythology who could constantly change his shape to avoid capture. It is a rare genetic mosaic disease, characterized by tissue overgrowth that can lead to irregular skeletal and vascular malformations and other life-threatening complications. The syndrome has been linked to mutations in the protein kinase Akt, which regulates cell growth, survival, and metabolism. Downstream of growth factor signaling, Akt is also frequently upregulated in cancer. The group of Thomas Leonard has previously shown that the activity of Akt is spatially restricted to membranes by the signaling lipids phosphatidylinositol-3,4,5-trisphosphate (PIP3) and phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2). In their latest study the scientists have determined the high-resolution structure of Akt1, revealing, in exquisite detail, the autoinhibitory interface that locks the kinase in an inactive conformation in the absence of signaling lipids. When not bound to PIP3 or PI(3,4)P2, the lipid binding domain blocks substrate binding to the kinase domain.
In addition to its activation by lipids, Akt must be phosphorylated on two sites within its kinase domain in order to be catalytically active. The scientists tested whether phosphorylation alone is enough to override the dependency on lipids. “Preparing stoichiometrically and site-specifically phosphorylated Akt was a huge technical challenge”, says lead author Linda Truebestein. Nevertheless, the researchers succeeded and could confirm the stoichiometry and site-specificity of Akt phosphorylation using mass spectrometry. The researchers’ data show that stoichiometric phosphorylation of Akt is insufficient to disrupt the autoinhibitory interface in the absence of signaling lipids. “Conceptually, this is in an important finding”, explains group leader Thomas Leonard. “It demonstrates that Akt doesn’t just get activated on membranes before dissociating into the cytosol to activate downstream effectors. It is, in fact, dependent on PIP3 or PI(3,4)P2, which restrict its activity to discrete membrane locations in the cell”.
Substitution of glutamate 17 with a lysine in the membrane-binding PH domain of Akt1 is associated with the majority of Proteus syndrome cases and has been identified in breast and ovarian cancers. With their high-resolution structure in hand, the scientists now found that glutamate 17 is buried in the autoinhibitory interface. “If a lysine is introduced at this position, it weakens the interface, which makes Akt more prone to activation by PIP3”, explains Thomas Leonard. “We now have a mechanistic explanation for how this point mutation in Akt leads to Proteus syndrome and some forms of cancer”.
Publication:
Linda Truebestein, Harald Hornegger, Dorothea Anrather, Markus Hartl, Kaelin D. Fleming, Jordan T.B. Stariha, Els Pardon, Jan Steyaert, John E. Burke, and Thomas A. Leonard: Structure of autoinhibited Akt1 reveals mechanism of PIP3-mediated activation. PNAS 2021
18th Microsymposium on RNA Biology
The „Microsymposium on RNA Biology“ is an international conference that brings together young scientists, junior and senior group leaders, and company representatives from all over the world to present and discuss their latest findings in the exciting field of small RNAs and beyond. The Microsymposium was founded in 2005 and has established itself as the major small RNA meeting in Europe. It is organized by the four research institutions IMBA, IMP, GMI and the Max Perutz Labs as well as by the RNA community of the Vienna BioCenter.
Nickel impact on human health, from bacterial infections to cancer
Multiscale plant bioimaging using advanced microscopy
Parthenogenesis, cryptobiosis, and the survival in extreme environmental conditions
Evading ageing: Mitochondrial and proteostatic adaptations in oocytes
Genomes in Rhodnius prolixus symbiotic system
Stem cells, immune evasion and metastasis in colorectal cancer
Ubiquitin & Friends Symposium 2024
The Ubiquitin & Friends Symposium is an annual international meeting taking place in the beautiful capital of Austria, aiming to bring together scholars from various fields studying ubiquitin/Ubl biology and protein degradation in a personal, family-like atmosphere, as suggested by the name.
The evolution and development of mollusc shells
Unraveling the Complexity of Crossover Regulation in C. elegans
Dynamics of 3D Genome Structure and Function
How superworms can help to solve our plastic waste crisis
Title to be announced
New players in an old pathway: biology of methanogens of the TACK superphylum
Shaping morphogen gradients: from molecules to tissues and back
Title to be announced
Studying stressed cells by in situ structural biology
Exploring Microbial Resilience: Unravelling Escherichia coliand#x27;s Stress Response at the Level of Protein Synthesis
Arbuscular mycorrhiza development and function
Deep homology and deep diversity: Evolving genetic toolkits for making and sensing light
The evolution of cell type identity and tissue microecology at the fetal-maternal interface
The unanticipated roles of PICIs and phages in bacterial evolution
Chemical targeting of subcellular protein localization
Origin and diversification of gut-derived organs in chordates
Job's Dilemma for the Genome: Why Bad Things Happen to Good Chromosomes
Connections between carbon and nitrogen cycling in the ocean
Understanding how the DNA-loop-extruding protein complex Condensin folds a chromatinized genome into mitotic chromosomes
From Roads to Rivers? Occurrence and environmental fate of tire and road wear particles and of tire-related chemicals
FENS 2024 Satellite event: Home cage behavior monitoring at the interface of animal welfare and neuroscience
Striking physiology and cell biology of (marine) environmental microorganisms
Mechanisms controlling maintenance of cohesin dependent loops
Title to be announced