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.
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.
|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|
|Dhungel, Nripesh; Eleuteri, Simona; Li, Ling-Bo et al. (2015) Parkinson's disease genes VPS35 and EIF4G1 interact genetically and converge on ?-synuclein. Neuron 85:76-87|
|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|
|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|
|Geller, Ron; Andino, Raul; Frydman, Judith (2013) Hsp90 inhibitors exhibit resistance-free antiviral activity against respiratory syncytial virus. PLoS One 8:e56762|
|Pechmann, Sebastian; Frydman, Judith (2013) Evolutionary conservation of codon optimality reveals hidden signatures of cotranslational folding. Nat Struct Mol Biol 20:237-43|
|Pechmann, Sebastian; Willmund, Felix; Frydman, Judith (2013) The ribosome as a hub for protein quality control. Mol Cell 49:411-21|
|Beltrao, Pedro; Albanèse, Véronique; Kenner, Lillian R et al. (2012) Systematic functional prioritization of protein posttranslational modifications. Cell 150:413-25|
|Geller, Ron; Taguwa, Shuhei; Frydman, Judith (2012) Broad action of Hsp90 as a host chaperone required for viral replication. Biochim Biophys Acta 1823:698-706|
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