# Regulation of Retinal cGMP-Phosphodiesterases

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $381,250

## Abstract

Project summary/Abstract
The long-term goal of this research program is to elucidate the molecular mechanisms
underlying the function and regulation of cGMP-phosphodiesterases (PDE6) in rods and
cones. PDE6 is a key effector enzyme in the phototransduction cascade. The clinical
importance of PDE6 is evident from the fact that its malfunction due to mutations in
genes encoding it or the specialized chaperone, aryl hydrocarbon receptor-interacting
protein-like 1 (AIPL1), lead to severe retinal diseases such as retinitis pigmentosa,
achromatopsia, and Leber congenital amaurosis (LCA). For many years progress in
understanding the structure and function of PDE6 has been hampered by a lack of an
effective heterologous expression system. The current proposal takes advantage of a
novel, robust system based on the co-expression of cone PDE6C with AIPL1 and the
inhibitory -subunit (P) in HEK293T cells. This system offers a unique opportunity to
gain mechanistic insights into the interaction between PDE6 and AIPL1 and their
client/chaperone relationship. Mutational analysis of PDE6C will be performed to identify
the structural determinants of the catalytic efficiency of PDE6 and to elucidate the
mechanisms whereby mutations lead to disease. We will test the hypothesis that many
pathogenic mutations disrupt the interaction of PDE6 with Pleading to markedly
diminished expression of functional PDE6. Using enzymatic activity as readout for the
AIPL1 chaperone function, we will examine the roles of AIPL1 domains and specific
partner interactions in the folding of PDE6, and delineate the mechanisms whereby
AIPL1 mutations cause LCA. We propose and will test a model in which P augments
expression of functional PDE6 by acting as an affinity adaptor for the AIPL1-PDE6
interaction during maturation of the enzyme. Our biochemical studies will be
complemented by structural analyses (X-ray crystallography and NMR) aimed at
obtaining a high-resolution structure of AIPL1 in complex with the PDE6 prenyl moiety
and P. This structure will signify an unprecedented advance in understanding AIPL1
and its interaction with PDE6. The ultimate goal of the proposed studies is to generate
critical insights into the mechanisms that underlie PDE6- and AIPL1-linked retinal
diseases, and to thereby contribute to the development of new therapeutic strategies.

## Key facts

- **NIH application ID:** 9994985
- **Project number:** 5R01EY010843-27
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Nikolai O Artemyev
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 1995-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994985

## Citation

> US National Institutes of Health, RePORTER application 9994985, Regulation of Retinal cGMP-Phosphodiesterases (5R01EY010843-27). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9994985. Licensed CC0.

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