# Protein Folding in the Eukaryotic Cytosol

> **NIH NIH R37** · STANFORD UNIVERSITY · 2020 · $521,650

## Abstract

Protein folding is a problem of the utmost basic and medical relevance, with important implications on our
understanding of protein structure, function, evolution and regulation. A better understanding of the cellular
pathways of protein folding will have important therapeutic applications impacting many devastating human
diseases. The transformation of the one-dimensional genetic information into three-dimensional protein
structures depends on the accuracy and efficiency of the process of protein folding. Folding in the cell differs
in three fundamental ways from the in vitro refolding experiments used to understand the principles of
chaperone mechanism and action under reductionistic paradigms. Firstly, in the cell protein folding must be
accomplished in the context of the vectorial synthesis of polypeptide chains on ribosomes. In principle, the
N-terminal portion of the nascent polypeptide could fold spontaneously as it emerges from the ribosome.
Secondly, it must take place in a crowded milieu, which heightens the chances of aggregation for unfolded
polypeptides. Given the high density of folding nascent chains emerging from polysomes and since unfolded
or partially folded polypeptide chains have a strong tendency to aggregate, it is critically important that the
growing polypeptide is effectively prevented from misfolding and aggregating until a chain length suitable for
productive folding has been synthesized. Thirdly, the cell contains many different chaperones, as well the
ubiquitin-proteasome degradation pathway, all of which are presumably vying for access to non-native
protein species. In the previous funding period we established that eukaryotic cells possess a complex
chaperone machinery that associates with translating ribosomes, and appears dedicated to protein
biogenesis. We aim to understand the principles and mechanisms by which these molecular chaperones
interact with, and stabilize, nascent polypeptides and assist their folding in vivo. The major thrusts of the
grant have been, and continue to be: (i) to integrate in vivo and in vitro approaches to define the substrates
and function of cotranslationally acting chaperones; (ii) to gain a mechanistic understanding of how these
chaperones bind to and fold nascent polypeptides and (iii) to understand the basis of chaperone interactions
with the translational machinery. In addition, we are beginning to explore the role of mRNA sequence (both
codon choice and UTR regions) in determining the fate of the nascent polypeptide.
RELEVANCE (See instructions):
The transformation of the one-dimensional genetic information into three-dimensional protein structures
depends on the accuracy and efficiency of the process of protein folding. Failure of correct protein folding is
associated with an increasing list of human maladies, ranging from neurodegeneration to cancer. The long
term goal of this program is to understand the process of protein folding as it occurs in the cell, where
proteins em...

## Key facts

- **NIH application ID:** 9873966
- **Project number:** 5R37GM056433-21
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Judith Frydman
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $521,650
- **Award type:** 5
- **Project period:** 1997-09-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873966

## Citation

> US National Institutes of Health, RePORTER application 9873966, Protein Folding in the Eukaryotic Cytosol (5R37GM056433-21). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9873966. Licensed CC0.

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