Suchergebnisse

This track sought to contribute to design's potential to shift, redirect and transform power relations to achieve sustainability. We sought to direct attention to the political potential in and politics of transition design with a focus on the many ways that power flows through the systems in which design operates. Our intention was to address, directly, the commentary from the DRS2018 track on Designing for Transitions, which noted that authors had tended to "stay on the safe and perhaps conventional side" of the subject. Instead, we hoped that the papers in this track would address "'politicised issues such as migration, decoloniality, the politics of climate change mitigation… and other complex and controversial problems" (Boehnert et al. 2018) that must be considered in planning and implementation of ongoing sustainability transitions. The politics of design transitions remains marginal in design research. With our call, we hoped to receive contributions that problematised design's current roles and conceptualised new roles for design in the context of sustainability transitions to attend to issues related to how power is and should be dealt with. ; publishedVersion ; This work is licensed under a Creative Commons Attribution-NonCommercialShare Alike 4.0 International License. https://creativecommons.org/licenses/by-nc-sa/4.0/

Abstract
Mediating the terminal reaction of gluconeogenesis and glycogenolysis, the integral membrane protein glucose-6-phosphate catalytic subunit 1 (G6PC1) regulates hepatic glucose production by catalyzing hydrolysis of glucose-6-phosphate (G6P) within the lumen of the endoplasmic reticulum. Consistent with its vital contribution to glucose homeostasis, inactivating mutations in G6PC1 causes glycogen storage disease (GSD) type 1a characterized by hepatomegaly and severe hypoglycemia. Despite its physiological importance, the structural basis of G6P binding to G6PC1 and the molecular disruptions induced by missense mutations within the active site that give rise to GSD type 1a are unknown. In this study, we determine the atomic interactions governing G6P binding as well as explore the perturbations imposed by disease-linked missense variants by subjecting an AlphaFold2 G6PC1 structural model to molecular dynamics simulations and in silico predictions of thermodynamic stability validated with robust in vitro and in situ biochemical assays. We identify a collection of side chains, including conserved residues from the signature phosphatidic acid phosphatase motif, that contribute to a hydrogen bonding and van der Waals network stabilizing G6P in the active site. The introduction of GSD type 1a mutations modified the thermodynamic landscape, altered side chain packing and substrate-binding interactions, and induced trapping of catalytic intermediates. Our results, which corroborate the high quality of the AF2 model as a guide for experimental design and to interpret outcomes, not only confirm the active-site structural organization but also identify previously unobserved mechanistic contributions of catalytic and noncatalytic side chains.