A complex association with cadmium
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FpnA, the Aspergillus fumigatus homolog of human ferroportin, mediates resistance to nickel, cobalt and gallium but does not function in iron homeostasis
Iron homeostasis is key to both the survival of virtually all organisms and the virulence of fungi including Aspergillus fumigatus, a human fungal pathogen causing life-threatening invasive infections. Unlike the extensively studied fungal species Saccharomyces cerevisiae and Schizosaccharomyces pombe, A. fumigatus encodes an uncharacterized homolog of vertebrate ferroportin (Fpn1), termed FpnA. Fpn1 is the only known vertebrate iron efflux transporter, while microbial organisms are thought to lack iron efflux systems. After correcting the exon-intron annotation, inactivation and conditional overexpression of the A. fumigatus FpnA-encoding gene (fpnA) indicated, that FpnA mediates resistance to nickel, cobalt and gallium but not to iron, aluminium, cadmium, copper or zinc. Functional N-terminal tagging with a fluorescent protein demonstrated localization of FpnA in the vacuolar membrane, suggesting that FpnA detoxifies substrate metals by vacuolar deposition. In line, overexpression of fpnA reduced the utilization of urea as a nitrogen source, most likely by depriving cytosolic urease of its essential cofactor nickel. Phylogenetic analysis illustrated conservation of FpnA in all fungal divisions and several other eukaryotic lineages, underlining its crucial role in metal homeostasis. The divergent localization and functionalization of ferroportin homologs in two phylogenetic sister groups, metazoa and fungi, is of particular evolutionary interest.
The WAVE complex in developmental and adulthood brain disorders
Actin polymerization and depolymerization are fundamental cellular processes required not only for the embryonic and postnatal development of the brain but also for the maintenance of neuronal plasticity and survival in the adult and aging brain. The orchestrated organization of actin filaments is controlled by various actin regulatory proteins. Wiskott‒Aldrich syndrome protein-family verprolin-homologous protein (WAVE) members are key activators of ARP2/3 complex-mediated actin polymerization. WAVE proteins exist as heteropentameric complexes together with regulatory proteins, including CYFIP, NCKAP, ABI and BRK1. The activity of the WAVE complex is tightly regulated by extracellular cues and intracellular signaling to execute its roles in specific intracellular events in brain cells. Notably, dysregulation of the WAVE complex and WAVE complex-mediated cellular processes confers vulnerability to a variety of brain disorders. De novo mutations in WAVE genes and other components of the WAVE complex have been identified in patients with developmental disorders such as intellectual disability, epileptic seizures, schizophrenia, and/or autism spectrum disorder. In addition, alterations in the WAVE complex are implicated in the pathophysiology of Alzheimer’s disease and Parkinson’s disease, as well as in behavioral adaptations to psychostimulants or maladaptive feeding.
Spin-state effect on the efficiency of a post-synthetic modification reaction on a spin crossover complex
The spin state of a metal center significantly influences the catalytic activity of its complex, a phenomenon so crucial that it has led to the dedicated field of spin catalysis. Here we investigate the effect of the spin state of an iron-based metal complex on the organic reactivity of its ligands. Specifically, we examined the post-synthetic modification of the spin crossover (SCO) complex [Fe(NH2trz)3](NO3)2 with p-anisaldehyde. A series of experiments were performed to study the transformation of the amino groups depending on the spin state of the metal. Owing to the wide thermal hysteresis loop of the SCO complex, both spin states were compared under identical conditions. The results revealed that the high-spin state led to the formation of 1.34 times more imine functional groups than the low-spin state, we propose that this arises from the different interactions between the solvent and the SCO at the different spin states.
Initiation of ERAD by the bifunctional complex of Mnl1/Htm1 mannosidase and protein disulfide isomerase
Misfolded glycoproteins in the endoplasmic reticulum (ER) lumen are translocated into the cytosol and degraded by the proteasome, a conserved process called ER-associated protein degradation (ERAD). In Saccharomyces cerevisiae, the glycan of these proteins is trimmed by the luminal mannosidase Mnl1 (Htm1) to generate a degradation signal. Interestingly, Mnl1 is associated with protein disulfide isomerase (Pdi1). Here we used cryo-electron microscopy, biochemical and in vivo experiments to elucidate how this complex initiates ERAD. The Mnl1–Pdi1 complex first demannosylates misfolded, globular proteins that are recognized through the C-terminal domain (CTD) of Mnl1; Pdi1 causes the CTD to ignore completely unfolded polypeptides. The disulfides of these globular proteins are then reduced by the Pdi1 component of the complex. Mnl1 blocks the canonical oxidative function of Pdi1, allowing it to function as a disulfide reductase in ERAD. The generated unfolded polypeptides can then be translocated across the membrane into the cytosol.
The structural basis for the human procollagen lysine hydroxylation and dual-glycosylation
The proper assembly and maturation of collagens necessitate the orchestrated hydroxylation and glycosylation of multiple lysyl residues in procollagen chains. Dysfunctions in this multistep modification process can lead to severe collagen-associated diseases. To elucidate the coordination of lysyl processing activities, we determine the cryo-EM structures of the enzyme complex formed by LH3/PLOD3 and GLT25D1/ColGalT1, designated as the KOGG complex. Our structural analysis reveals a tetrameric complex comprising dimeric LH3/PLOD3s and GLT25D1/ColGalT1s, assembled with interactions involving the N-terminal loop of GLT25D1/ColGalT1 bridging another GLT25D1/ColGalT1 and LH3/PLOD3. We further elucidate the spatial configuration of the hydroxylase, galactosyltransferase, and glucosyltransferase sites within the KOGG complex, along with the key residues involved in substrate binding at these enzymatic sites. Intriguingly, we identify a high-order oligomeric pattern characterized by the formation of a fiber-like KOGG polymer assembled through the repetitive incorporation of KOGG tetramers as the biological unit.
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