A PAR6–aPKC–LGL structure reveals how LGL antagonizes aPKC
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Memristors based on two-dimensional h-BN materials: synthesis, mechanism, optimization and application
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T-cell receptor structures and predictive models reveal comparable alpha and beta chain structural diversity despite differing genetic complexity
T-cell receptor (TCR) structures are currently under-utilised in early-stage drug discovery and repertoire-scale informatics. Here, we leverage a large dataset of solved TCR structures from Immunocore to evaluate the current state-of-the-art for TCR structure prediction, and identify which regions of the TCR remain challenging to model. Through clustering analyses and the training of a TCR-specific model capable of large-scale structure prediction, we find that the alpha chain VJ-recombined loop (CDR3α) is as structurally diverse and correspondingly difficult to predict as the beta chain VDJ-recombined loop (CDR3β). This differentiates TCR variable domain loops from the genetically analogous antibody loops and supports the conjecture that both TCR alpha and beta chains are deterministic of antigen specificity. We hypothesise that the larger number of alpha chain joining genes compared to beta chain joining genes compensates for the lack of a diversity gene segment. We also provide over 1.5M predicted TCR structures to enable repertoire structural analysis and elucidate strategies towards improving the accuracy of future TCR structure predictors. Our observations reinforce the importance of paired TCR sequence information and capture the current state-of-the-art for TCR structure prediction, while our model and 1.5M structure predictions enable the use of structural TCR information at an unprecedented scale.
Dact1 induces Dishevelled oligomerization to facilitate binding partner switch and signalosome formation during convergent extension
Convergent extension (CE) is a universal morphogenetic engine that promotes polarized tissue extension. In vertebrates, CE is regulated by non-canonical Wnt ligands signaling through “core” proteins of the planar cell polarity (PCP) pathway, including the cytoplasmic protein Dishevelled (Dvl), receptor Frizzled (Fz) and tetraspan protein Van gogh-like (Vangl). PCP was discovered in Drosophila to coordinate polarity in the plane of static epithelium, but does not regulate CE in flies. Existing evidence suggests that adopting PCP for CE might be a vertebrate-specific adaptation with incorporation of new regulators. Herein we use Xenopus to investigate Dact1, a chordate-specific protein. Dact1 induces Dvl to form oligomers that dissociate from Vangl, but stay attached with Fz as signalosome-like clusters and co-aggregate with Fz into protein patches upon non-canonical Wnt induction. Functionally, Dact1 antagonizes Vangl, and synergizes with wild-type Dvl but not its oligomerization-defective mutants. We propose that, by promoting Dvl oligomerization, Dact1 couples Dvl binding partner switch with signalosome-like cluster formation to initiate non-canonical Wnt signaling during vertebrate CE.
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