A5056575777- PI3K/AKT/mTOR signaling in cancer
- Chronic Lymphocytic Leukemia Research
- Circadian rhythm and melatonin
- Light effects on plants
- Protein Kinase Regulation and GTPase Signaling
- Ubiquitin and proteasome pathways
- CRISPR and Genetic Engineering
- Plant Molecular Biology Research
- Biochemical and Molecular Research
- Hippo pathway signaling and YAP/TAZ
- Cellular transport and secretion
- Enzyme Structure and Function
- Neurobiology and Insect Physiology Research
- Bioactive Compounds and Antitumor Agents
- Spaceflight effects on biology
- Genomics and Rare Diseases
- Advanced Electron Microscopy Techniques and Applications
- Plant Reproductive Biology
- Enzyme function and inhibition
- Genetics, Bioinformatics, and Biomedical Research
- Chemical Reactions and Isotopes
- Peptidase Inhibition and Analysis
- Bacteriophages and microbial interactions
- Click Chemistry and Applications
MRC Laboratory of Molecular Biology
2009-2021
Medical Research Council
2010-2017
Max Planck Institute of Molecular Physiology
2005-2013
Max Planck Society
2005-2007
Cryptochromes are flavoproteins that evolutionary related to the DNA photolyases but lack repair activity. Drosophila cryptochrome (dCRY) is a blue light photoreceptor involved in synchronization of circadian clock with environmental light-dark cycle. Until now, spectroscopic and structural studies on this other animal cryptochromes have largely been hampered by difficulties their recombinant expression. We therefore established an expression purification scheme enables us purify mg amounts...
Mastering regulation The mechanistic target of rapamycin complex 1 (mTORC1) is known as the master kinase, acknowledging its key role in integrating multiple signals to regulate cell growth. When nutrients are abundant, heterodimers Rag, a class small guanosine triphosphatase, bind mTORC1 and recruit it lysosome. Here, other signaling pathways converge on complex. Anandapadamanaban et al. determined cryo–electron microscopy crystal structures RagA/RagC heterodimer. structures, together with...
Phosphoinositide 3-kinase δ is upregulated in lymphocytic leukemias. Because the p85-regulatory subunit binds to any class IA subunit, it was assumed there a single universal p85-mediated regulatory mechanism; however, we find isozyme-specific inhibition by p85α. Using deuterium exchange mass spectrometry (DXMS), mapped interactions of p110δ with Both nSH2 and cSH2 domains p85α contribute full p110δ, contacting helical domain via C terminus p110δ. The inhibits p110β but not p110α, implying...
Abstract The target of rapamycin (Tor) is a Ser/Thr protein kinase that regulates range anabolic and catabolic processes. Tor present in two complexes, TORC1 TORC2, which the Tor–Lst8 heterodimer forms common sub-complex. We have determined cryo-electron microscopy (EM) structure bound to Lst8. Two heterodimers assemble further into dyad-symmetry dimer mediated by Tor–Tor interactions. first 1,300 residues form HEAT repeat-containing α -solenoid with four distinct segments: highly curved...
Cryo-Electron Microscopy (cryo-EM) is a pivotal tool for determining the 3D structures of biological macromolecules. Current cryo-EM workflows, while effective, are computationally demanding and require manual intervention, creating bottlenecks use in high-throughput scenarios such as structure-based drug discovery. Often discovery, one can assume that all instances protein equivalent at resolutions needed alignment it therefore should be possible to harness information about particle poses...
Abstract Activation of the phosphoinositide 3‐kinase (PI3K) pathway is a key signaling event in cancer, inflammation, and other proliferative diseases. PI3K inhibitors are already approved for some specific clinical indications, but their systemic on‐target toxicity limits larger use. In particular, whereas tolerable acute treatment life‐threatening diseases, this less acceptable chronic conditions. past, strategy to overcome drawback was block selected isoforms mainly expressed leukocytes,...
The mTORC1 kinase complex regulates cell growth, proliferation, and survival. Because mis-regulation of DEPTOR, an endogenous inhibitor, is associated with some cancers, we reconstituted DEPTOR to understand its function. We find that a unique partial inhibitor may have evolved preserve feedback inhibition PI3K. Counterintuitively, activated by RHEB or oncogenic mutation much more potently inhibited DEPTOR. Although partially inhibits mTORC1, prevents this phosphorylating mutual antagonism...
Correction for: Hoang N, Schleicher E, Kacprzak S, Bouly JP, Picot M, et al. (2008) Human and Drosophila cryptochromes are light activated by flavin photoreduction in living cells. PLoS Biol 6(7): e160. doi:10.1371/journal.pbio.0060160 The seventh author's name appears incorrectly. It should be: Alex Berndt.
Abstract Eukaryotic cells coordinate growth with the availability of nutrients through protein kinase complex mTORC1, which is part a pathway that often upregulated in cancer. The mTORC1 activated by association two types GTPases, Rags and RHEB. heterodimeric Rag GTPases are key components activation response to amino acids. heterodimer interacts RAPTOR subunit manner dependent on nucleotide-bound states its constituent GTPases. We used hydrogen/deuterium exchange mass spectrometry (HDX-MS)...
Abstract mTORC1 is a kinase complex regulating cell growth, proliferation and survival. Because mis-regulation of DEPTOR, an endogenous inhibitor, associated with some cancers, we reconstituted DEPTOR to understand its function. We find that unique partial inhibitor may have evolved preserve feedback inhibition PI3K. Counterintuitively, activated by RHEB or oncogenic mutation much more potently inhibited DEPTOR. Although partially inhibits mTORC1, prevents this phosphorylating mutual...