Protein kinases are enzymes that catalyze the phosphorylation of other proteins, thereby regulating their conformation, subcellular localization and activity. Microtubule-associated Ser/Thr kinases (MAST) have recently been identified to be the causative factor underlying the neurodevelopmental disorder Mega Corpus Callosum with Cerebellar Hypoplasia and Cortical Malformations (MCC-CH-CM). The lab of Thomas Leonard will take an integrative structural biology and biochemistry approach, allied with complementary cell biological and organismal work in the lab of their collaborators, to investigate the regulation and function of MAST. “Next to nothing is known about MAST kinases beyond their interaction with microtubules and the recent discovery of their involvement in MCC-CH-CM,” says Thomas Leonard. “We expect our findings to be interesting to biochemists, developmental biologists and clinicians alike”.
Members of apolipoprotein B mRNA editing enzymes, or APOBEC, are important viral restriction factors. In contrast to their function in healthy cells, studies in cancer patients indicate that the ability of APOBECs to hypermutate DNA can have detrimental effects in humans by driving mutations in cancers. Cells have therefore developed mechanisms to keep APOBECs in check, but detailed insight into these regulatory controls is currently lacking. Gijs Versteeg’s lab now aims to identify novel regulators of APOBEC enzymes and clarify the pathways by which they are degraded. “This will provide insight into nuclear control mechanisms ensuring genome stability and could help to understand how APOBECs contribute to cancer and therapy resistance”, says Gijs Versteeg.
The endoplasmic reticulum (ER) and the nucleus are the two largest compartments within our cells. The nucleus is separated from the rest of the cell by the nuclear membrane, which is continuous with the ER membrane. The connectivity between the two organelles is crucial for cells to transduce signals to the nucleus for maintaining homeostasis and to supply new lipids and membrane proteins to the nucleus for growth and repair. How the shape and number of the connections change to support key cellular functions, and which molecules regulate the connections is poorly understood. “We will use a novel high-resolution microscopy approach, combined with quantitative live cell imaging and molecular perturbations to reveal the structure and function of these connections”, says Shotaro Otsuka.