In cancer, the programmed death-1 (PD-1) pathway suppresses T cell stimulation and mediates immune escape. Upon stimulation, PD-1 becomes phosphorylated at its immune receptor tyrosine–based inhibitory motif (ITIM) and immune receptor tyrosine–based switch motif (ITSM), which then bind the Src homology 2 (SH2) domains of SH2-containing phosphatase 2 (SHP2), initiating T cell inactivation. The SHP2–PD-1 complex structure and the exact functions of the two SH2 domains and phosphorylated motifs remain unknown. Here, we explain the structural basis and provide functional evidence for the mechanism of PD-1-mediated SHP2 activation. We demonstrate that full activation is obtained only upon phosphorylation of both ITIM and ITSM: ITSM binds C-SH2 with strong affinity, recruiting SHP2 to PD-1, while ITIM binds N-SH2, displacing it from the catalytic pocket and activating SHP2. This binding event requires the formation of a new inter-domain interface, offering opportunities for the development of novel immunotherapeutic approaches.
We summarize investigations on four different nematic main-chain elastomer systems. In the first part, the synthetic approaches towards nematic elastomers with clearing temperatures suitable for mechanical investigations are described. In the second part, the coupling between the liquid crystalline order and the chain conformation is quantified by the Landau-de Gennes coefficient U. Comparing different types of elastomers shows that the coupling depends on the type of mesogens forming the polymer backbone, and on the elastic modulus of the polymer network. In the third part, we compare the orientation behavior of the different systems under strain.
Summary: The behavior of the complex shear modulus G = G′ + iG″ of a main chain liquid crystalline elastomer film oriented with the director in the plane of the film is investigated for the first time by shearing the film in a direction perpendicular or parallel to the director. The film exhibits a small mechanical anisotropy around the N‐I transition, which disappears slightly above TNI. A hydrodynamic softening of both G′⟂ and G′∥ (symbols ∥ and ⟂ refer to the direction of the director parallel, respectively perpendicular, to the shear displacement) is observed in the isotropic phase near TNI which is ascribed to the reorientation of the SmC domains revealed by X‐rays. These SmC domains are frozen‐in the temperature range investigated. They relax with a characteristic time which is deduced from the frequency dependence of the mechanical response of the film. It is shown that the time‐temperature superposition method does not apply and that there is no indication in favor of soft or semi‐soft elasticity. The influence of a static compression induced either mechanically on the film or by the shape change of the film as a function of temperature is also investigated. Data on the polydomain analogue complement this study.Temperature dependence of G′∥ and G′⟂ at 0.2 Hz for the monodomain film.imageTemperature dependence of G′∥ and G′⟂ at 0.2 Hz for the monodomain film.
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