The paper presents new developments and amendments to the ATSAS package (version 2.4) for processing and analysis of isotropic small-angle scattering data.

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The class III receptor tyrosine kinase (RTKIII) Fms-like tyrosine kinase receptor 3 (Flt3) and its cytokine ligand (FL) play central roles in hematopoiesis and the immune system, by establishing signaling cascades crucial for the development and homeostasis of hematopoietic progenitors and antigen-presenting dendritic cells. However, Flt3 is also one of the most frequently mutated receptors in hematologic malignancies and is currently a major prognostic factor and clinical target for acute myeloid leukemia. IntroductionHematopoiesis is a finely regulated process during which diverse cell types originating from a limited and self-renewing population of hematopoietic stem cells (HSCs) are stimulated to proliferate and differentiate to create the cellular repertoire that sustains the mammalian hematopoietic and immune systems. 1 The Fms-like tyrosine kinase receptor 3 (Flt3) is the most recent addition to the diverse family of hematopoietic receptors. Flt3 is activated on HSCs and early myeloid and lymphoid progenitors by its cognate ligand (FL), to initiate downstream signaling via the phosphatidylinositol 3-kinase/AKT and the Ras/Raf/extracellular signal-regulated kinase pathways. 2,3 Consistent with the narrow expression profile of Flt3 in the bone marrow environment, signaling via the Flt3 ligand-receptor complex primarily impacts early hematopoiesis, particularly the proliferation and development of HSC and B-cell progenitors. 2,4 In recent years, Flt3 and FL emerged as potent regulators of dendritic cell (DC) development and homeostasis, [5][6][7] and DC-mediated natural killer cell activation, 8 thereby gaining an important role at the interface of innate and acquired immunity and in cancer immunotherapy. 9,10 Notably, Flt3/FL-driven DC generation yields both classic and plasmacytoid DCs from bone marrow progenitors regardless of myeloid or lymphoid commitment, a property that is currently unmatched by any other receptor-cytokine system relevant for DC physiology. 11,12 Flt3 is a class III receptor tyrosine kinase (RTKIII) together with the prototypic platelet-derived growth factor receptors-␣/␤, colony-stimulating factor 1 receptor (CSF-1R), and KIT. 13 Thus, Flt3 has been predicted to display a modular structure featuring an extracellular segment with 5 immunoglobulin (Ig)-like domains (residues 27-543), a single transmembrane (TM) helix (residues 544-563), a cytoplasmic juxtamembrane domain ([JM]; residues 572-603), and a split intracellular kinase module (residues 604-958). The RTKIII family is closely related to the RTKV family of vascular endothelial growth factor receptors (VEGFRs), which have 7 extracellular Ig-like domains. The hallmark of RTKIII/V signaling lies in the activation of the extracellular receptor segments on binding of the cognate cytokines, followed by intermolecular autophosphorylation and activation of the intracellular kinase domains. 14 Besides the clear role of Flt3 signaling in hematopoiesis and immune system development, overexpression of wild-type or oncogenic forms of Flt3 h...

The bifunctional major autolysin Atl plays a key role in staphylococcal cell separation. Processing of Atl yields catalytically active amidase (AM) and glucosaminidase (GL) domains that are each fused to repeating units. The two repeats of AM (R1 and R2) target the enzyme to the septum, where it cleaves murein between dividing cells. We have determined the crystal structure of R2, which reveals that each repeat folds into two half-open ␤-barrel subunits. We further demonstrate that lipoteichoic acid serves as a receptor for the repeats and that this interaction depends on conserved surfaces in each subunit. Small-angle X-ray scattering of the mature amidase reveals the presence of flexible linkers separating the AM, R1, and R2 units. Different levels of flexibility for each linker provide mechanistic insights into the conformational dynamics of the full-length protein and the roles of its components in cell wall association and catalysis. Our analysis supports a model in which the repeats direct the catalytic AM domain to the septum, where it can optimally perform the final step of cell division.

BackgroundTardigrades represent an animal phylum with extraordinary resistance to environmental stress.ResultsTo gain insights into their stress-specific adaptation potential, major clusters of related and similar proteins are identified, as well as specific functional clusters delineated comparing all tardigrades and individual species (Milnesium tardigradum, Hypsibius dujardini, Echiniscus testudo, Tulinus stephaniae, Richtersius coronifer) and functional elements in tardigrade mRNAs are analysed. We find that 39.3% of the total sequences clustered in 58 clusters of more than 20 proteins. Among these are ten tardigrade specific as well as a number of stress-specific protein clusters. Tardigrade-specific functional adaptations include strong protein, DNA- and redox protection, maintenance and protein recycling. Specific regulatory elements regulate tardigrade mRNA stability such as lox P DICE elements whereas 14 other RNA elements of higher eukaryotes are not found. Further features of tardigrade specific adaption are rapidly identified by sequence and/or pattern search on the web-tool tardigrade analyzer http://waterbear.bioapps.biozentrum.uni-wuerzburg.de. The work-bench offers nucleotide pattern analysis for promotor and regulatory element detection (tardigrade specific; nrdb) as well as rapid COG search for function assignments including species-specific repositories of all analysed data.ConclusionDifferent protein clusters and regulatory elements implicated in tardigrade stress adaptations are analysed including unpublished tardigrade sequences.