No abstract

The exceptional mechanical properties of the load-bearing connection of tendon to bone rely on an intricate interplay of its biomolecular composition, microstructure and micromechanics. Here we identify that the Achilles tendon-bone insertion is characterized by an interface region of ∼500 μm with a distinct fibre organization and biomolecular composition. Within this region, we identify a heterogeneous mechanical response by micromechanical testing coupled with multiscale confocal microscopy. This leads to localized strains that can be larger than the remotely applied strain. The subset of fibres that sustain the majority of loading in the interface area changes with the angle of force application. Proteomic analysis detects enrichment of 22 proteins in the interfacial region that are predominantly involved in cartilage and skeletal development as well as proteoglycan metabolism. The presented mechanisms mark a guideline for further biomimetic strategies to rationally design hard-soft interfaces.

This review focuses on chemical probes to identify the protein binding partners of natural products in living systems.

Helicobacter pylori specifically colonizes the human gastric epithelium and is the major causative agent for ulcer disease and gastric cancer development. Here we identified members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family as novel receptors of H. pylori and show that HopQ is the surface-exposed adhesin that specifically binds human CEACAM1, CEACAM3, CEACAM5 and CEACAM6. HopQ-CEACAM binding is glycan-independent and targeted to the N-domain. H. pylori binding induces CEACAM1 mediated signaling, and the HopQ-CEACAM1 interaction enables translocation of the virulence factor CagA into host cells, and enhances the release of proinflammatory mediators such as interleukin-8. Based on the crystal structure of HopQ, we found that a β-hairpin insertion (HopQ-ID) in HopQ's extracellular 3+4 helix bundle domain is important for CEACAM binding. A peptide derived from this domain competitively inhibits HopQ-mediated activation of the Cag virulence pathway, as genetic or antibodymediated abrogation of the HopQ function shows. Together, our data imply the HopQ-CEACAM1 interaction as potentially promising novel therapeutic target to combat H. pyloriassociated diseases. Helicobacter pylori (H. pylori) is one of the most prevalent human pathogens, colonizing half of the world's population. Chronic inflammation elicited by this bacterium is the main cause of gastric cancer 1. During co-evolution with it's human host over more than 60.000 years 2 , the bacterium has acquired numerous adaptations for the long-term survival within its unique niche, the stomach. This includes the ability to buffer the extreme acidity of this environment, the interference with cellular signaling pathways, the evasion of the human immune response and a strong adhesive property to host cells 3. Specifically, H. pylori persistence is facilitated by the binding of BabA and SabA adhesins to the human blood group antigen Leb and the sLex antigen, respectively 4-6. However, adhesion to blood group antigens is not universal, is dynamically regulated during the course of infection and can also be turned off 7. We observed that H. pylori was capable of binding to human gastric epithelium of nonsecretors. Therefore, we hypothesized that the bacterium might be able to interact with other cell surface receptors to ensure persistent colonization. We here show that the H. pylori adhesin HopQ specifically interacts with human carcinoembryonic antigen-related cell adhesion molecules (CEACAMs). CEACAMs embrace a group of immunoglobulin superfamily-related glycoproteins with a wide tissue distribution. CEACAM1 can be expressed in leukocytes, endothelial and epithelial cells, CEACAM3 and CEACAM8 in granulocytes, CEACAM5 and CEACAM7 in epithelial cells and CEACAM6 in epithelia and granulocytes. In epithelial cells, transmembrane anchored CEACAM1 as well as glycosylphosphatidylinositol-linked CEACAM5, CEACAM6 and CEACAM7 localize to the apical membrane 8. CEACAMs modulate diverse cellular functions such as cell adhesion, differentiation,...