# Coordination of chaperone interactions that dictate protein folding and trafficking

> **NIH NIH R35** · VANDERBILT UNIVERSITY · 2020 · $394,786

## Abstract

PROJECT SUMMARY
 Proteins fold into their 3-dimensional shape with the help of chaperones and other protein folding
factors, which together comprise the proteostasis network (PN). During the protein quality control
process, transient binding interactions between individual client proteins and proteostasis factors mediate
folding into native functional structures, thereby ensuring trafficking to the correct cellular destination, or
facilitating degradation of detrimental misfolded states. Consequently, imbalances in interactions
between proteostasis factors and clients proteins result in quality control defects that lead to diverse
protein misfolding diseases including highly prevalent neurodegenerative diseases such as Alzheimer’s
and Parkinson’s Disease. The folding, maturation and trafficking of large multi-domain and multi-subunits
proteins is a complex and highly client-specific process that depends on engaging the appropriate
component of the PN at the correct time. Many proteostasis dependencies for individual client proteins,
are known, but little is understood about the order of engagement, and whether correct sequential
interactions are required for proper folding and trafficking. Understanding the coordination of the PN
interaction with client proteins at an organelle- or cell-wide level will be crucial to determine the
mechanisms of quality control defects that impact protein misfolding diseases.
 We utilize the power of chemical biology and quantitative proteomics tools to determine the
interaction dynamics between disease-associated protein variants and the PN. This enables us to
investigate the mechanism by which altered progression through the PN impacts protein quality control.
To probe the progression of the client proteins through protein folding and trafficking pathways, we will
establish new proteomics methodology to elucidate dynamically changing interactions both globally and
in a time-dependent manner. We will examine the coordination requirement of different proteostasis
pathways as they affect protein aggregation (thryroglobulin) and loss-of-function protein misfolding
(cystic fibrosis transmembrance conductance regulator – CFTR). Aggregation of destabilized
thyroglobulin variants, a thyroid hormone precursor, is a leading cause for congenital hypothyroidism,
while misfolding and pre-mature degradation of CFTR variants is the primary cause of Cystic Fibrosis. In
particular, we will assess how protein quality control of mutant variants of these proteins is impacted by
altered PN interactions and how established and new approaches to manipulate proteostasis pathways
can correct these quality control defects. Results from our studies will provide significant new insights
into how the dynamics of protein folding and trafficking pathways can be manipulated therapeutically for
disease intervention.

## Key facts

- **NIH application ID:** 10000953
- **Project number:** 5R35GM133552-02
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Lars Plate
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $394,786
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000953

## Citation

> US National Institutes of Health, RePORTER application 10000953, Coordination of chaperone interactions that dictate protein folding and trafficking (5R35GM133552-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10000953. Licensed CC0.

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