01992nas a2200205   4500008004100000022001400041245010600055210006900161260007900230300001400309490000800323520120900331100001801540700002001558700002101578700001801599700002001617700002401637856012501661       2015                        eng d  a0006-349500aMolecular mechanism underlying recruitment and insertion of lipid-anchored LC3 protein into membranes0 aMolecular mechanism underlying recruitment and insertion of lipi  a600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USAbCELL PRESScNOV  a2067-20780 v1093 a<p>Lipid modification of cytoplasmic proteins initiates membrane engagement that triggers diverse cellular processes. Despite the abundance of lipidated proteins in the human proteome, the key determinants underlying membrane recognition and insertion are poorly understood. Here, we define the course of spontaneous membrane insertion of LC3 protein modified with phosphatidylethanolamine using multiple coarse-grain simulations. The partitioning of the lipid anchor chains proceeds through a concerted process, with its two acyl chains inserting one after the other. Concurrently, a conformational rearrangement involving the alpha-helix III of LC3, especially in the three basic residues Lys(65), Arg(68), and Arg(69), ensures stable insertion of the phosphatidylethanolamine anchor into membranes. Mutational studies validate the crucial role of these residues, and further live-cell imaging analysis shows a substantial reduction in the formation of autophagic vesicles for the mutant proteins. Our study captures the process of water-favored LC3 protein recruitment to the membrane and thus opens, to our knowledge, new avenues to explore the cellular dynamics underlying vesicular trafficking.</p>1 aThukral, Lipi1 aSengupta, Durba1 aRamkumar, Amrita1 aMurthy, Divya1 aAgrawal, Nikhil1 aGokhale, Rajesh, S.  uhttps://library.ncl.res.in/content/molecular-mechanism-underlying-recruitment-and-insertion-lipid-anchored-lc3-protein-002449nas a2200325   4500008004100000022001400041245010200055210006900157260000800226300001300234490000700247520140400254100001901658700001801677700001801695700002001713700002301733700002001756700001801776700001801794700001801812700002601830700001901856700001901875700002701894700002201921700002501943700002401968856013101992       2022                        eng d  a1544-917300aTemporal analysis of melanogenesis identifies fatty acid metabolism as key skin pigment regulator0 aTemporal analysis of melanogenesis identifies fatty acid metabol  cMAY  ae30016340 v203 a<p>
	Therapeutic methods to modulate skin pigmentation has important implications for skin cancer prevention and for treating cutaneous hyperpigmentary conditions. Towards defining new potential targets, we followed temporal dynamics of melanogenesis using a cell-autonomous pigmentation model. Our study elucidates 3 dominant phases of synchronized metabolic and transcriptional reprogramming. The melanogenic trigger is associated with high MITF levels along with rapid uptake of glucose. The transition to pigmented state is accompanied by increased glucose channelisation to anabolic pathways that support melanosome biogenesis. SREBF1-mediated up-regulation of fatty acid synthesis results in a transient accumulation of lipid droplets and enhancement of fatty acids oxidation through mitochondrial respiration. While this heightened bioenergetic activity is important to sustain melanogenesis, it impairs mitochondria lately, shifting the metabolism towards glycolysis. This recovery phase is accompanied by activation of the NRF2 detoxication pathway. Finally, we show that inhibitors of lipid metabolism can resolve hyperpigmentary conditions in a guinea pig UV-tanning model. Our study reveals rewiring of the metabolic circuit during melanogenesis, and fatty acid metabolism as a potential therapeutic target in a variety of cutaneous diseases manifesting hyperpigmentary phenotype.</p>
1 aSultan, Farina1 aBasu, Reelina1 aMurthy, Divya1 aKochar, Manisha1 aAttri, Kuldeep, S.1 aAggarwal, Ayush1 aKumari, Pooja1 aDnyane, Pooja1 aTanwar, Jyoti1 aMotiani, Rajender, K.1 aSingh, Archana1 aGadgil, Chetan1 aBhavesh, Neel, Sarovar1 aSingh, Pankaj, K.1 aNatarajan, Vivek, T.1 aGokhale, Rajesh, S.  uhttps://library.ncl.res.in/content/temporal-analysis-melanogenesis-identifies-fatty-acid-metabolism-key-skin-pigment-regulator