Clathrin-coated vesicles transport selected integral membrane proteins from the cell surface and the trans-Golgi network to the endosomal system. Before fusing with their target the vesicles must be stripped of their coats. This process is effected by the chaperone protein hsp70c together with a 100K cofactor which we here identify as the coat protein auxilin. Auxilin binds with high affinity to assembled clathrin lattices and, in the presence of ATP, recruits hsp70c. Dissociation of the lattice does not depend as previously supposed on clathrin light chains or on the amino-terminal domain of the heavy chain. The presence of a J-domain at its carboxy terminus now defines auxilin as a member of the DnaJ protein family. In conjunction with hsp70, DnaJ proteins catalyse protein folding, protein transport across membranes and the selective disruption of protein-protein interactions. We show that deletion of the J-domain of auxilin results in the loss of cofactor activity.
Key Points• IDH1 promotes leukemogenesis in vivo in cooperation with HoxA9.• Pharmacologic inhibition of mutant IDH1 efficiently inhibits AML cells of IDH1-mutated patients but not of normal CD34 1 bone marrow cells.Mutations in the metabolic enzymes isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are frequently found in glioma, acute myeloid leukemia (AML), melanoma, thyroid cancer, and chondrosarcoma patients. Mutant IDH produces 2-hydroxyglutarate (2HG), which induces histone-and DNA-hypermethylation through inhibition of epigenetic regulators. We investigated the role of mutant IDH1 using the mouse transplantation assay. Mutant IDH1 alone did not transform hematopoietic cells during 5 months of observation. However, mutant IDH1 greatly accelerated onset of myeloproliferative disease-like myeloid leukemia in mice in cooperation with HoxA9 with a mean latency of 83 days compared with cells expressing HoxA9 and wild-type IDH1 or a control vector (167 and 210 days, respectively, P 5 .001). Mutant IDH1 accelerated cell-cycle transition through repression of cyclindependent kinase inhibitors Cdkn2a and Cdkn2b, and activated mitogen-activated protein kinase signaling. By computational screening, we identified an inhibitor of mutant IDH1, which inhibited mutant IDH1 cells and lowered 2HG levels in vitro, and efficiently blocked colony formation of AML cells from IDH1-mutated patients but not of normal CD341 bone marrow cells. These data demonstrate that mutant IDH1 has oncogenic activity in vivo and suggest that it is a promising therapeutic target in human AML cells. (Blood.
On-surface synthesis constitutes a rapidly growing field of research due to its promising application for creating stable molecular structures on surfaces. While self-assembled structures rely on reversible interactions, on-surface synthesis provides the potential for creating long-term stable structures with well-controlled properties, for example superior electron transport for future molecular electronic devices. On-surface synthesis holds the promise for preparing insoluble compounds that cannot be produced in solution. Another highly exciting aspect of on-surface synthesis is the chance to discover new reaction pathways due to the two-dimensional confinement of the reaction educts. In this review, we discuss the current state-of-the-art and classify the reactions that have been successfully performed so far. Special emphasis is put on electrically insulating surfaces, as these substrates pose particular challenges for on-surface synthesis while at the same time bearing high potential for future use, for example, in molecular electronics.
The anoxygenic phototrophic bacterium Rhodobacter sphaeroides uses different energy sources depending on environmental conditions including aerobic respiration or, in the absence of oxygen, photosynthesis. Photosynthetic genes are repressed at high oxygen tension, but at intermediate levels their partial expression prepares the organism for using light energy. Illumination, however, enhances repression under semi-aerobic conditions. Here, we describe molecular details of two proteins involved in oxygen- and light-control of photosynthesis gene expression, the light-sensing anti-repressor AppA and the transcriptional repressor PpsR. We combine information from crystal structures of both proteins and their complex with hydrogen-deuterium exchange data to show that light-activation of AppA–PpsR2 affects the PpsR effector region within the complex. DNA-binding studies demonstrate the formation of a light-sensitive ternary AppA–PpsR–DNA complex. Implications of these results for light- and oxygen-regulation are discussed, highlighting new insights into blue-light-mediated signal transduction.
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