The Membrane-Associated Proteins FCHo and SGIP Are Allosteric Activators of the AP2 Clathrin Adaptor Complex

The AP2 clathrin adaptor complex links protein cargo to the endocytic machinery but it is unclear how AP2 is activated on the plasma membrane. Here we demonstrate that the membrane-associated proteins FCHo and SGIP1 convert AP2 into an open, active conformation. We screened for C. elegans mutants that phenocopy the loss of AP2 subunits and found that AP2 remains inactive in fcho-1 mutants. A subsequent screen for bypass suppressors of fcho-1 nulls identified 71 compensatory mutations in all four AP2 subunits. Using a protease-sensitivity assay we show that these mutations restore the open conformation in vivo. The domain of FCHo that induces this rearrangement is not the F-BAR domain or the mu-homology domain, but rather is an uncharacterized 90 amino acid motif, found in both FCHo and SGIP proteins, that directly binds AP2. Thus, these proteins stabilize nascent endocytic pits by exposing membrane and cargo binding sites on AP2

Ultraviolet Irradiation Induces the Accumulation of Chondroitin Sulfate, but Not Other Glycosaminoglycans, in Human Skin

Ultraviolet (UV) light alters cutaneous structure and function. Prior work has shown loss of dermal hyaluronan after UV-irradiation of human skin, yet UV exposure increases total glycosaminoglycan (GAG) content in mouse models. To more fully describe UV-induced alterations to cutaneous GAG content, we subjected human volunteers to intermediate-term (5 doses/week for 4 weeks) or single-dose UV exposure. Total dermal uronyl-containing GAGs increased substantially with each of these regimens. We found that UV exposure substantially increased dermal content of chondroitin sulfate (CS), but not hyaluronan, heparan sulfate, or dermatan sulfate. UV induced the accumulation of both the 4-sulfated (C4S) and 6-sulfated (C6S) isoforms of CS, but in distinct distributions. Next, we examined several CS proteoglycan core proteins and found a significant accumulation of dermal and endothelial serglycin, but not of decorin or versican, after UV exposure. To examine regulation in vitro, we found that UVB in combination with IL-1α, a cytokine upregulated by UV radiation, induced serglycin mRNA in cultured dermal fibroblasts, but did not induce the chondroitin sulfate synthases. Overall, our data indicate that intermediate-term and single-dose UVB exposure induces specific GAGs and proteoglycan core proteins in human skin in vivo. These molecules have important biologic functions and contribute to the cutaneous response to UV

Milk Lacking α-Casein Leads to Permanent Reduction in Body Size in Mice

The major physiological function of milk is the transport of amino acids, carbohydrates, lipids and minerals to mammalian offspring. Caseins, the major milk proteins, are secreted in the form of a micelle consisting of protein and calcium-phosphate

Vesicules recouvertes, polypeptides d'assemblage et phosphorylation

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Etude pharmaco-toxicologique de l'acide hyaluronique de haut poids moléculaire (modulation in vitro et in vivo de la toxicité de xénobiotiques au niveau de la surface oculaire)

L objectif de cette thèse est d explorer les propriétés pharmacologiques de l acide hyaluronique (AH), un biopolymère souvent utilisé pour ses propriétés physico-chimiques, dans le cadre d une nouvelle stratégie thérapeutique de modulation des effets toxiques de différents xénobiotiques au niveau de la surface oculaire. Les travaux réalisés sur des modèles in vitro et in vivo mettent en évidence que l AH de haut poids moléculaire module la toxicité du chlorure de benzalkonium (conservateur incriminé dans plusieurs pathologies oculaires iatrogènes), du laurylsulfate de sodium (irritant de référence pour les études réglementaires de toxicité oculaire) et des radiations UVB (responsable de traumatismes de la surface oculaire). Cette modulation a pour origine une activité pharmacologique de l AH imputable à des effets antiapoptotiques et anti-inflammatoires observés in vitro qui expliquerait ainsi le rôle protecteur de l AH vis-à-vis de la surface oculaire observé in vivo.Hyaluronan (HA) is a biopolymer used as a therapeutical agent for its chemo-physical properties. The aim of this thesis was to investigate the pharmacological properties of high molecular weight HA. In vitro and in vivo data indicate that high molecular weight HA has significant protective effects against benzalkonium chloride (a preservative incriminated in several iatrogenic pathologies), sodium laurylsulfate (toxic used in reglementary studies of ocular toxicity), and UVB radiations (responsible for traumas of the ocular surface). This modulation is attributable to pharmacological activities of HA, with antiapoptotic and anti-inflammatory effects we observed in vitro, which could explain the ocular surface-protective role of HA we observed in vivo.PARIS-BIUP (751062107) / SudocSudocFranceF

Etude de la biogenèse des gouttelettes lipidiques dans la cellule épithéliale mammaire : effet de la PRL et de l’EGF, importance de la voie PI3k-Akt-mTOR

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