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      Structures of human Patched and its complex with native palmitoylated sonic hedgehog

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      Nature
      Springer Nature America, Inc

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          Targeting the Hedgehog pathway in cancer.

          Several key signalling pathways, such as Hedgehog, Notch, Wnt and BMP-TGFbeta-Activin (bone morphogenetic protein-transforming growth factor-beta-Activin), are involved in most processes essential to the proper development of an embryo. It is also becoming increasingly clear that these pathways can have a crucial role in tumorigenesis when reactivated in adult tissues through sporadic mutations or other mechanisms. We will focus here on the Hedgehog pathway, which is abnormally activated in most basal cell carcinomas, and discuss potential therapeutic opportunities offered by the progress made in understanding this signalling pathway.
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            Patched acts catalytically to suppress the activity of Smoothened.

            Mutations affecting the transmembrane proteins Patched (Ptc) or Smoothened (Smo) that trigger ligand-independent activity of the Hedgehog (Hh) signalling pathway are associated with human tumours such as basal cell carcinoma (BCC) and medulloblastoma. Despite extensive genetic studies demonstrating the importance of these receptor components in embryonic patterning and cancer, the mechanism by which Ptc regulates Smo is not understood. Here we report that Ptc and Smo are not significantly associated within Hh-responsive cells. Furthermore, we show that free Ptc (unbound by Hh) acts sub-stoichiometrically to suppress Smo activity and thus is critical in specifying the level of pathway activity. Patched is a twelve-transmembrane protein with homology to bacterial proton-driven transmembrane molecular transporters; we demonstrate that the function of Ptc is impaired by alterations of residues that are conserved in and required for function of these bacterial transporters. These results suggest that the Ptc tumour suppressor functions normally as a transmembrane molecular transporter, which acts indirectly to inhibit Smo activity, possibly through changes in distribution or concentration of a small molecule.
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              Alignment of cryo-EM movies of individual particles by optimization of image translations.

              Direct detector device (DDD) cameras have revolutionized single particle electron cryomicroscopy (cryo-EM). In addition to an improved camera detective quantum efficiency, acquisition of DDD movies allows for correction of movement of the specimen, due to both instabilities in the microscope specimen stage and electron beam-induced movement. Unlike specimen stage drift, beam-induced movement is not always homogeneous within an image. Local correlation in the trajectories of nearby particles suggests that beam-induced motion is due to deformation of the ice layer. Algorithms have already been described that can correct movement for large regions of frames and for >1 MDa protein particles. Another algorithm allows individual <1 MDa protein particle trajectories to be estimated, but requires rolling averages to be calculated from frames and fits linear trajectories for particles. Here we describe an algorithm that allows for individual <1 MDa particle images to be aligned without frame averaging or linear trajectories. The algorithm maximizes the overall correlation of the shifted frames with the sum of the shifted frames. The optimum in this single objective function is found efficiently by making use of analytically calculated derivatives of the function. To smooth estimates of particle trajectories, rapid changes in particle positions between frames are penalized in the objective function and weighted averaging of nearby trajectories ensures local correlation in trajectories. This individual particle motion correction, in combination with weighting of Fourier components to account for increasing radiation damage in later frames, can be used to improve 3-D maps from single particle cryo-EM.
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                Author and article information

                Journal
                Nature
                Nature
                Springer Nature America, Inc
                0028-0836
                1476-4687
                August 2018
                July 11 2018
                August 2018
                : 560
                : 7716
                : 128-132
                Article
                10.1038/s41586-018-0308-7
                29995851
                c53bb0c2-75c4-4b10-84a9-de0e458ed6fa
                © 2018

                http://www.springer.com/tdm

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