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An optical pulse-chase system shows differences in the half-lives of mutant huntingtin protein, depending on the neuronal type, helping to explain how certain subsets of neurons are more susceptible to Huntington's disease. The changes in protein clearance can be attributed to cell type-specific differences in proteostasis mechanisms, represented here as a tiger, determining the longevity of a neuron (tree). Cover art by Erin Dewalt, based on original artwork by Maria Zhalnina, inspired by Dalì's Dream Caused by the Flight of a Bee Around a Pomegranate a Second Before Awakening, The Three Sphinxes of Bikini and The Persistence of Memory. Article, p586
Vitamin B12–dependent radical enzymes that can undergo irreversible inactivation during catalysis have their own chaperones for the maintenance of catalytic activities. New research defines a mobile loop in the G protein that determines chaperone function and defines a switch III motif akin to that found in classical G proteins.
Analysis of the yeast ATP-binding cassette transporter interactome provides insight relevant to human health on the regulation and function of a protein family that determines tolerance to physiological conditions and externally imposed stress.
DNA in the cytosol activates immune responses by binding sensors such as cGAMP synthase (cGAS). A set of studies reveal the structural mechanism of DNA sensing and show that cGAS produces a cyclic 2′-5′-linked dinucleotide, a new cellular second messenger.
Heterotrimeric G proteins contain a switch III motif that regulates enzyme function. Structural and biochemical studies now identify a similar switch III loop in a nonheterotrimeric G-protein chaperone that explains the debilitating effects of mutations linked to methylmalonic aciduria.
Structural and thermodynamic characterization of the interaction between the intrinsically disordered HBV protein preS1 and the human adaptor protein γ2-EAR indicates that the viral protein imitates host cell interaction motifs to gain access to the cellular trafficking system.
The VCP ATPase has been linked to cancer, but the lack of well-defined, selective inhibitors has limited further investigation. A million-molecule screen now identifies a covalent inhibitor as well as an allosteric inhibitor that may freeze the enzyme in an ADP-bound conformation.
An inhibitor of oxysterol-induced Smoothened activation defines a 20-OHC binding site in the extracellular domain of this essential component of the Hedgehog signaling pathway.
Mapping the yeast ABC transporter interactome suggests functional significance of transporter-transporter interactions and also shows function of some transporters in zinc homeostasis.
LuxR receptor and LuxI synthase homologs coordinate quorum sensing in several bacterial species. Investigations of a LuxR family member that is missing a LuxI partner define a pheromone signaling circuit that coordinates cell clumping based on recognition of its newly discovered ligands, the photopyrones.
A small-molecule activator of Wnt/β-catenin signaling acts by binding a negative regulator of β-catenin, Axin, leading to a conformational change that promotes association of Axin with LRP6.
Monitoring the half-life of mutant huntingtin protein reveals how specific neurons are more susceptible to its toxic effects and to Huntington's disease.