# Structural basis for chaperone-dependent folding of beta-propeller proteins essential for vision

> **NIH NIH R01** · BRIGHAM YOUNG UNIVERSITY · 2022 · $46,273

## Abstract

PROJECT SUMMARY
 The cytosolic chaperonin CCT is a large protein complex that plays an indispensable role in maintaining the
cellular proteome by assisting in the folding of numerous proteins with complex tertiary structures and
unfavorable folding trajectories. Proper CCT function is vital to human vision as evidenced by the fact that
inactivating mutations in CCT cause Leber Congenital Amaurosis (LCA). CCT contributes to the visual
process by folding the cytoskeletal proteins actin and tubulin as well as a number of proteins with b-propeller
folds that have essential functions in the visual process. These include the G protein b1 (Gb1) subunit of the
visual G protein transducin, the G protein b5 (Gb5) subunit of the regulator of G protein signaling 9 (RGS9)
dimer, and the BBS2, BBS7 and BBS9 subunits of the Bardet-Biedl syndrome (BBSome) ciliary transport
complex. In this proposal, we present evidence for a new function of CCT in the folding of human RPE65,
another b-propeller protein that is a key enzyme in the visual cycle, the process that converts the all-trans
retinol product of the light response back to 11-cis retinal to regenerate rhodopsin and maintain vision. Despite
the importance of CCT in maintaining the proteome, we know very little at the molecular level about how CCT
assists in the folding of these b-propeller proteins and how mutations in these proteins disrupt folding and cause
disease. To address this gap in knowledge, we propose to use high resolution cryo-EM to determine the
structures of key intermediates in the folding of human RPE65 and Gb5. These structures will tell us at the
molecular level how CCT interacts with RPE65 and Gb5 to enable their folding. Furthermore, we propose to
determine the structure of RPE65 and Gb5 folding mutants bound to CCT to learn how the mutations disrupt the
folding trajectory and trap the mutant proteins inside CCT in an unfolded state. These studies will provide new
insight into the molecular defects that cause misfolding of the RPE65 and Gb5 mutants and will establish a
foundation for structure-based drug design to create new therapies for LCA and other retinopathies caused by
these mutations.

## Key facts

- **NIH application ID:** 10652005
- **Project number:** 3R01EY012287-20S1
- **Recipient organization:** BRIGHAM YOUNG UNIVERSITY
- **Principal Investigator:** BARRY M WILLARDSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,273
- **Award type:** 3
- **Project period:** 1999-05-03 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10652005

## Citation

> US National Institutes of Health, RePORTER application 10652005, Structural basis for chaperone-dependent folding of beta-propeller proteins essential for vision (3R01EY012287-20S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10652005. Licensed CC0.

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