Adressage des protéines

Résumé

Dans une cellule, la localisation d'une protéine est essentielle à son bon fonctionnement. Or le lieu de production d'une protéine est souvent différent de son lieu d'action. L'adressage est l'ensemble des mécanismes qui permettent à une protéine d'être dirigée vers la bonne position. Les ARNm sont sujet à un adressage. Günter Blobel, biologiste moléculaire germano-américain, a obtenu le Prix Nobel de physiologie ou médecine en 1999 pour ses travaux sur la NLS (nuclear localisation signal), une séquence en acides aminés permettant aux protéines qui la portent d'être importée dans le noyau grâce à des importines. Signal d'adressage Peptide signal Le signal d'adressage est une courte séquence d'acide aminés non polaires, généralement situé à l'extrémité N-terminale de la protéine, servant à désigner les protéines devant être adressées, et indiquer leur destination. Bien que très répandus, les signaux d'adressage ne sont pas une caractéristique universelle, par exemple, les p

Source officielle

https://fr.wikipedia.org/wiki/Adressage_des_prot%C3%A9ines

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Asymmetric Cell Division in the Skin

Wan-Hung Fan

An asymmetric cell division (ACD) is defined as a division that gives rise to two daughter cells with different fates. It is the most common type of division during development. Analogous to Drosophila neuroblasts, proteins involved in ACD such as Insc and LGN are found to be asymmetrically localized during perpendicular cell divisions in mammalian skin, suggesting that the cutaneous tissue homeostasis may be controlled by using similar mechanisms. Most cell divisions in the basal layer of the skin are perpendicular to the basal membrane (BM), but when a skin tumor is formed, most cell divisions would become parallel to the BM. Previous studies in our lab have shown that regressing skin tumor caused by β-catenin depletion have increased perpendicular cell divisions accompanied by reduced stem cell numbers and enhanced mTrim2 expression. Furthermore, induced expression of mTRIM2 in skin tumors led to tumor regression. Taken together, this suggests that progenitor cells in the basal layer of the epidermis may use vertical ACDs to maintain progenitor cell number while using horizontal SCDs to expand progenitor cell number and mTrim2 may function as a cell fate determinant in skin. To validate the hypothesis that vertical divisions of basal keratinocytes to the BM are ACDs, I utilized light sheet based fluorescence microscopy (LSFM) to perform the time lapse recording of murine embryonic skin development between E14.5 and E17.5 and to monitor individual dividing cells and to track their fates after division. For visualizing the dividing cells, protein localization and differentiating cells, I have generated several transgenic mouse lines and combined them together. My study showed that ACD of basal keratinocytes can be either vertical or horizontal to the BM and divisions in the suprabasal layer can be both ACDs and SCDs. To study the potential function of mTRIMs in skin, I generated the knock-out (KO) mice. Neither mTrim2 KO, mTrim3 KO or mTrim32 KO mice showed any phenotype in skin, therefore I combined these mice to generate mTrim2/3 double KO and mTrim2/3/32 triple KO mice. Still, no skin phenotype was observed in these mice, indicating that mTrim2/3/32 might not function as a cell fate determinant in skin.

EPFL2012

Chargement

Engineering Agrobacterium tumefaciens Adhesion to Target Cells

Zaïnebe Al-Mayyah, Alexandre Louis André Persat, Alix Kim Lan Pham, Xavier Jean-Yves Pierrat, Jeremy Pak Hei Wong

Agrobacterium tumefaciens is a plant pathogen commonly repurposed for genetic modification of crops. Despite its versatility, it remains inefficient at transferring DNA to many hosts, including to animal cells. Like many pathogens, physical contact between A. tumefaciens and host cells promotes infection efficacy. Thus, improving the strength and specificity of A. tumefaciens to target cells has the potential for enhancing DNA transfer for biotechnological and therapeutic purposes. Here, we demonstrate a methodology for engineering genetically encoded exogeneous adhesins at the surface of A. tumefaciens. We identified an autotransporter gene we named Aat that is predicted to show canonical beta-barrel and passenger domains. We engineered the beta-barrel scaffold and linker (Aat(beta)) to display synthetic adhesins susceptible to rewire A. tumefaciens to alternative host targets. As a proof of concept, we leveraged the versatility of a VHH domain to rewire A. tumefaciens adhesion to yeast and mammalian hosts displaying a GFP target receptor. Finally, to demonstrate how synthetic A. tumefaciens adhesion can improve transfer to host cells, we showed improved protein translocation into HeLa cells using a sensitive split luciferase reporter system. Engineering A. tumefaciens adhesion has therefore a strong potential in generating complex heterogeneous cellular assemblies and in improving DNA transfer efficiency against non-natural hosts.

AMER CHEMICAL SOC2022

Chargement

Metal based anti-cancer drugs (metallodrugs) such as cisplatin are a cornerstone of cancer chemotherapy. However, development of this class of compound has been hindered by our lack of understanding of how they function. This is mainly because existing method to study the mechanism of action of metallodrugs are lacking as they were either directly adapted from methods to study organic drugs which have very different chemical properties or current limits in technology and knowledge were a bottleneck to the development of suitable methods. Mass spectrometry (MS) has emerged as a powerful tool which can be applied to study the mechanism of action of metallodrugs. Many different MS methods exist which can be adapted to study different aspects of drug action while accounting for the unique chemical nature of metallodrugs. In this dissertation, we develop MS strategies to study how platinum and ruthenium metallodrugs work and study a few important aspects of their function. Firstly, the in vitro distribution of and ligand state of metallodrugs were studied by imaging mass spectrometry. Next, we attempted to find novel protein targets of metallodrugs using a novel protein expression profiling approach. Promising metallodrug protein targets obtained from this study were then validated via biochemical methods. To facilitate the application of MS based protein-metallodrug fragmentation experiments for finding binding sites of metallodrugs on proteins, we developed and optimized web-based tools for automatic processing of complex spectra from these experiment. We then applied these tools to study the interaction of metallodrugs on relevant proteins, which provided insight into the specific binding properties of metallodrugs on proteins.

EPFL2016

Chargement

Asymmetric Cell Division in the Skin

Wan-Hung Fan

EPFL2012