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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM078024-13
Application #
9856441
Study Section
Membrane Biology and Protein Processing Study Section (MBPP)
Program Officer
Ainsztein, Alexandra M
Project Start
2007-09-28
Project End
2020-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
13
Fiscal Year
2020
Total Cost
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Kobayashi, Kan; Jomaa, Ahmad; Lee, Jae Ho et al. (2018) Structure of a prehandover mammalian ribosomal SRP┬ĚSRP receptor targeting complex. Science 360:323-327
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
Jomaa, Ahmad; Fu, Yu-Hsien Hwang; Boehringer, Daniel et al. (2017) Structure of the quaternary complex between SRP, SR, and translocon bound to the translating ribosome. Nat Commun 8:15470
Chen, Yang; Shen, Kuang; Shan, Shu-Ou et al. (2016) Analyzing Single-Molecule Protein Transportation Experiments via Hierarchical Hidden Markov Models. J Am Stat Assoc 111:951-966
Shan, Shu-Ou (2016) ATPase and GTPase Tangos Drive Intracellular Protein Transport. Trends Biochem Sci 41:1050-1060
Ariosa, Aileen; Lee, Jae Ho; Wang, Shuai et al. (2015) Regulation by a chaperone improves substrate selectivity during cotranslational protein targeting. Proc Natl Acad Sci U S A 112:E3169-78
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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