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Lipids Regulate Lck Protein Activity through Their Interactions with the Lck Src Homology 2 Domain
Sheng, Ren,Jung, Da-Jung,Silkov, Antonina,Kim, Hyunjin,Singaram, Indira,Wang, Zhi-Gang,Xin, Yao,Kim, Eui,Park, Mi-Jeong,Thiagarajan-Rosenkranz, Pallavi,Smrt, Sean,Honig, Barry,Baek, Kwanghee,Ryu, Sung American Society for Biochemistry and Molecular Bi 2016 The Journal of biological chemistry Vol.291 No.34
<P>Lymphocyte-specific protein-tyrosine kinase (Lck) plays an essential role in T cell receptor (TCR) signaling and T cell development, but its activation mechanism is not fully understood. To explore the possibility that plasma membrane (PM) lipids control TCR signaling activities of Lck, we measured the membrane binding properties of its regulatory Src homology 2 (SH2) and Src homology 3 domains. The Lck SH2 domain binds anionic PM lipids with high affinity but with low specificity. Electrostatic potential calculation, NMR analysis, and mutational studies identified the lipid-binding site of the Lck SH2 domain that includes surface-exposed basic, aromatic, and hydrophobic residues but not the phospho-Tyr binding pocket. Mutation of lipid binding residues greatly reduced the interaction of Lck with the chain in the activated TCR signaling complex and its overall TCR signaling activities. These results suggest that PM lipids, including phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate, modulate interaction of Lck with its binding partners in the TCR signaling complex and its TCR signaling activities in a spatiotemporally specific manner via its SH2 domain.</P>
Chen, Y.,Sheng, R.,Kallberg, M.,Silkov, A.,Tun, Moe P.,Bhardwaj, N.,Kurilova, S.,Hall, Randy A.,Honig, B.,Lu, H.,Cho, W. Cell Press 2012 Molecular cell Vol.46 No.2
Emerging evidence indicates that membrane lipids regulate protein networking by directly interacting with protein-interaction domains (PIDs). As a pilot study to identify and functionally annodate lipid-binding PIDs on a genomic scale, we performed experimental and computational studies of PDZ domains. Characterization of 70 PDZ domains showed that ~40% had submicromolar membrane affinity. Using a computational model built from these data, we predicted the membrane-binding properties of 2,000 PDZ domains from 20 species. The accuracy of the prediction was experimentally validated for 26 PDZ domains. We also subdivided lipid-binding PDZ domains into three classes based on the interplay between membrane- and protein-binding sites. For different classes of PDZ domains, lipid binding regulates their protein interactions by different mechanisms. Functional studies of a PDZ domain protein, rhophilin 2, suggest that all classes of lipid-binding PDZ domains serve as genuine dual-specificity modules regulating protein interactions at the membrane under physiological conditions.
Kim, D.,Park, M.J.,Gwon, G.,Silkov, A.,Xu, Z.Y.,Yang, E.,Song, S.,Song, K.,Kim, Y.,Yoon, H.,Honig, B.,Cho, W.,Cho, Y.,Hwang, I. Cell Press 2014 DEVELOPMENTAL CELL Vol.30 No.5
In organellogenesis of the chloroplast from endosymbiotic cyanobacteria, the establishment of protein-targeting mechanisms to the chloroplast should have been pivotal. However, it is still mysterious how these mechanisms were established and how they work in plant cells. Here we show that AKR2A, the cytosolic targeting factor for chloroplast outer membrane (COM) proteins, evolved from the ankyrin repeat domain (ARD) of the host cell by stepwise extensions of its N-terminal domain and that two lipids, monogalactosyldiacylglycerol (MGDG) and phosphatidylglycerol (PG), of the endosymbiont were selected to function as the AKR2A receptor. Structural analysis, molecular modeling, and mutational analysis of the ARD identified two adjacent sites for coincidental and synergistic binding of MGDG and PG. Based on these findings, we propose that the targeting mechanism of COM proteins was established using components from both the endosymbiont and host cell through a modification of the protein-protein-interacting ARD into a lipid binding domain.