The proposed research aims at a precise molecular understanding of how certain classes of proteins are selectively targeted to and translocated across the endoplasmic reticulum membrane in mammalian cells. We will identify the cellular constituents of the protein targeting and translocation machinery that are essential, and ultimately also those that are modulatory, to gain a detailed understanding of the mechanism of targeting and translocation and the role which individual molecules play in this fundamentally important process. Specifically, i) we will determine the molecular details of signal recognition particle (SRP) - signal sequence interactions and SRP-ribosome interactions and ask how these interactions are regulated. ii) We will determine the individual contribution of each of the three GTPase domains contained in the SRP and the SRP receptor during protein targeting to the endoplasmic reticulum membrane and the assembly of the protein translocation site. We will design assays to identify other molecules that affect the binding and/or hydrolysis of GTP by individual GTPase domains. iii) We will determine the minimal set of ER proteins that is required for nascent chain targeting, nascent chain insertion and nascent chain translocation and try to decipher the mechanistic role that these protein play in the process. The proposed research is clearly of a most basic nature and there is no doubt that it will be of profound significance for an understanding of physiology and pathology at the cellular and molecular level.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Shapiro, Bert I
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Elvekrog, Margaret M; Walter, Peter (2015) Dynamics of co-translational protein targeting. Curr Opin Chem Biol 29:79-86
Noriega, Thomas R; Chen, Jin; Walter, Peter et al. (2014) Real-time observation of signal recognition particle binding to actively translating ribosomes. Elife 3:
Noriega, Thomas R; Tsai, Albert; Elvekrog, Margaret M et al. (2014) Signal recognition particle-ribosome binding is sensitive to nascent chain length. J Biol Chem 289:19294-305
Lin, Jonathan H; Li, Han; Zhang, Yuhong et al. (2009) Divergent effects of PERK and IRE1 signaling on cell viability. PLoS One 4:e4170
Reyes, Christopher L; Rutenber, Earl; Walter, Peter et al. (2007) X-ray structures of the signal recognition particle receptor reveal targeting cycle intermediates. PLoS One 2:e607
Shan, Shu-ou; Chandrasekar, Sowmya; Walter, Peter (2007) Conformational changes in the GTPase modules of the signal reception particle and its receptor drive initiation of protein translocation. J Cell Biol 178:611-20
Shan, Shu-ou; Walter, Peter (2005) Molecular crosstalk between the nucleotide specificity determinant of the SRP GTPase and the SRP receptor. Biochemistry 44:6214-22
Credle, Joel J; Finer-Moore, Janet S; Papa, Feroz R et al. (2005) On the mechanism of sensing unfolded protein in the endoplasmic reticulum. Proc Natl Acad Sci U S A 102:18773-84
Shan, Shu-ou; Walter, Peter (2003) Induced nucleotide specificity in a GTPase. Proc Natl Acad Sci U S A 100:4480-5
Papa, Feroz R; Zhang, Chao; Shokat, Kevan et al. (2003) Bypassing a kinase activity with an ATP-competitive drug. Science 302:1533-7

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