Proper localization of proteins is crucial for all cells. The signal recognition particle (SRP) and its receptor (SR) constitute the major cellular machinery that mediates the co-translational targeting of roughly one third of cellular proteins to the eukaryotic endoplasmic reticulum, or the bacterial plasma membrane. Although enormous progress has been made in understanding the simplest SRP in bacteria, eukaryotic SRP is four times larger and contains five additional protein subunits. Compared to bacterial SRP, our understanding of the more complex mammalian SRP lags far behind. In this grant cycle, we will establish a rigorous mechanistic framework for the mammalian SRP pathway and decipher the role of eukaryote-specific components in this particle. We will interrogate the molecular mechanisms by which the SRP receptor interacts with and exerts regulatory functions at the membrane in both the bacterial and mammalian SRP pathways. Understanding the mammalian SRP pathway will likely unravel new layers of regulation in higher eukaryotic cells. Comparison between the bacterial and mammalian SRP will reveal general principles that enable the balance between efficiency and accuracy in both organisms, and shed light on the interplay between protein and RNA during the evolution of ancient ribonucleoprotein particles. The proposed research is of a most basic nature, and will contribute profoundly to our general understanding of physiology and pathology of all living cells at the molecular level.
The proper localization of proteins to the correct cellular destination is essential for establishing order and organization in all cells. The Signal Recognition Particle is a universally conserved protein targeting machinery that mediates the proper localization of ~30% of cellular proteins to the target membranes. The proposed studies will significantly advance our understanding of the mechanism of membrane protein localization and biogenesis within the cell, and contribute profoundly to our general understanding of physiology and pathology of all living cells at a molecular level.
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|Lee, Jae Ho; Chandrasekar, Sowmya; Chung, SangYoon et al. (2018) Sequential activation of human signal recognition particle by the ribosome and signal sequence drives efficient protein targeting. Proc Natl Acad Sci U S A 115:E5487-E5496|
|Hwang Fu, Yu-Hsien; Huang, William Y C; Shen, Kuang et al. (2017) Two-step membrane binding by the bacterial SRP receptor enable efficient and accurate Co-translational protein targeting. Elife 6:|
|Wang, Shuai; Yang, Chien-I; Shan, Shu-Ou (2017) SecA mediates cotranslational targeting and translocation of an inner membrane protein. J Cell Biol 216:3639-3653|
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|von Loeffelholz, Ottilie; Jiang, Qiyang; Ariosa, Aileen et al. (2015) Ribosome-SRP-FtsY cotranslational targeting complex in the closed state. Proc Natl Acad Sci U S A 112:3943-8|
|Guo, Huan; Xiong, Yi; Witkowski, Piotr et al. (2014) Inefficient translocation of preproinsulin contributes to pancreatic ? cell failure and late-onset diabetes. J Biol Chem 289:16290-302|
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