The long term goal of this Research Program is to understand how newly translated proteins fold in eukaryotic cells. The proposed research will focus on folding events as they occur at the ribosome during synthesis of a polypeptide and will examine the role of molecular chaperones in their folding process. The conceptual framework for understanding de novo protein folding originates from our work in the previous funding cycle, which showed that a network of chaperones named CLIPS (Chaperones Linked to Protein Synthesis) is physically and functionally linked to the translation machinery. Our working hypothesis is that the CLIPS chaperones are tasked with guiding newly synthesized polypeptides to their folded conformation. Chaperone-mediated folding pathways appear to involve the cooperation of different classes of CLIPS, including chaperones that act early in the folding process, such as the Nascent Chain Associated Complex (NAC), the Hsp70 proteins and the GIM/prefoldin complex, and the mechanistically distinct chaperones TRiC/CCT and Hsp90, which appear to act later in the folding process. Our general strategy to elucidate how chaperones mediate the folding of newly synthesized proteins relies on the close integration of in vitro and in vivo approaches. Our proposed experiments are aimed at obtaining functional, mechanistic and structural insights into the role of chaperones in de novo folding.

Public Health Relevance

Protein folding is a key step in the expression of the genetic information. Failure to fold correctly leads to accumulation of misfolded proteins and loss of protein function, which has been associated with many pathological states. The long term goal of this Research Program is to understand how newly translated proteins fold in eukaryotic cells. Our general strategy to elucidate how chaperones mediate the folding of newly synthesized proteins relies on the close integration of in vitro and in vivo approaches. Our proposed experiments are aimed at obtaining functional, mechanistic and structural insights into the role of chaperones in de novo folding.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37GM056433-14
Application #
8578833
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Wehrle, Janna P
Project Start
1997-09-01
Project End
2018-02-28
Budget Start
2013-07-01
Budget End
2014-02-28
Support Year
14
Fiscal Year
2013
Total Cost
$398,992
Indirect Cost
$132,992
Name
Stanford University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Pechmann, Sebastian; Frydman, Judith (2014) Interplay between chaperones and protein disorder promotes the evolution of protein networks. PLoS Comput Biol 10:e1003674