The long term goal of this proposal is to understand the biochemistry and cell biology of protein folding in eukaryotic cells. The general strategy will be to concentrate on the folding of two model proteins, actin and luciferase. 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 the folding process. The conceptual framework to understand the folding of proteins during translation originates from the applicant's earlier work, which indicates that the newly translated polypeptides are guided to their final conformation through a sequential and highly coupled chaperone pathway. This pathway combines two distinct principles of chaperone action, namely the Hsp70/Hsp40 proteins that act by stabilizing extended polypeptides, and the chaperonin TRiC, which by virtue of its ring-like structure creates an environment that is favorable for polypeptide chain folding. The objective of the proposal is to investigate critical aspects of the folding of newly synthesized proteins by: 1) defining the complement of chaperones that interact with nascent chains as the polypeptide length increases, 2) assessing the requirement of individual chaperone proteins in the folding of newly synthesized proteins and determine whether folding occurs in association with the chaperone complex, 3) investigating the role of the translational apparatus and possible novel components in the recruitment of chaperones to the nascent chains, and 4) examining the interaction of chaperones with newly translated polypeptides in intact mammalian cells.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Biochemistry Study Section (BIO)
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Stanford University
Schools of Arts and Sciences
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Sontag, Emily Mitchell; Samant, Rahul S; Frydman, Judith (2017) Mechanisms and Functions of Spatial Protein Quality Control. Annu Rev Biochem 86:97-122
Hanebuth, Marie A; Kityk, Roman; Fries, Sandra J et al. (2016) Multivalent contacts of the Hsp70 Ssb contribute to its architecture on ribosomes and nascent chain interaction. Nat Commun 7:13695
Chartron, Justin W; Hunt, Katherine C L; Frydman, Judith (2016) Cotranslational signal-independent SRP preloading during membrane targeting. Nature 536:224-8
Shen, Koning; Calamini, Barbara; Fauerbach, Jonathan A et al. (2016) Control of the structural landscape and neuronal proteotoxicity of mutant Huntingtin by domains flanking the polyQ tract. Elife 5:
Pechmann, Sebastian; Chartron, Justin W; Frydman, Judith (2014) Local slowdown of translation by nonoptimal codons promotes nascent-chain recognition by SRP in vivo. Nat Struct Mol Biol 21:1100-5
Pechmann, Sebastian; Frydman, Judith (2014) Interplay between chaperones and protein disorder promotes the evolution of protein networks. PLoS Comput Biol 10:e1003674
Sontag, Emily Mitchell; Vonk, Willianne I M; Frydman, Judith (2014) Sorting out the trash: the spatial nature of eukaryotic protein quality control. Curr Opin Cell Biol 26:139-146
Duttler, Stefanie; Pechmann, Sebastian; Frydman, Judith (2013) Principles of cotranslational ubiquitination and quality control at the ribosome. Mol Cell 50:379-93
Geller, Ron; Andino, Raul; Frydman, Judith (2013) Hsp90 inhibitors exhibit resistance-free antiviral activity against respiratory syncytial virus. PLoS One 8:e56762
Willmund, Felix; del Alamo, Marta; Pechmann, Sebastian et al. (2013) The cotranslational function of ribosome-associated Hsp70 in eukaryotic protein homeostasis. Cell 152:196-209

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