The integrity and organization AIPL1.pdf (1.71 MB)
The integrity and organization of the human AIPL1 functional domains is critical for its role as a HSP90-dependent co-chaperone for rod PDE6
journal contribution
posted on 2023-06-09, 08:15 authored by Almudena Sacristan-Reviriego, James Bellingham, Chrisostomos ProdromouChrisostomos Prodromou, Neruban Kumaran, James Bainbridge, Michel Michaelides, Jacqueline van der SpuyBiallelic mutations in the photoreceptor-expressed aryl hydrocarbon receptor interacting protein-like 1 (AIPL1) are associated with autosomal recessive Leber congenital amaurosis (LCA), the most severe form of inherited retinopathy in early childhood. AIPL1 functions as a photoreceptor-specific co-chaperone that interacts with the molecular chaperone HSP90 to facilitate the stable assembly of the retinal cyclic GMP (cGMP) phosphodiesterase (PDE6) holoenzyme. In this study, we characterized the functional deficits of AIPL1 variations, some of which induce aberrant pre-mRNA AIPL1 splicing leading to the production of al- ternative AIPL1 isoforms. We investigated the ability of the AIPL1 variants to mediate an interaction with HSP90 and modulate the rod cGMP PDE6 stability and activity. Our data revealed that both the FK506 binding protein (FKBP)-like domain and the tetra- tricopeptide repeat (TPR) domain of AIPL1 are required for interaction with HSP90. We further demonstrate that AIPL1 signifi- cantly modulates the catalytic activity of heterologously expressed rod PDE6. Although the N-terminal FKBP-like domain of AIPL1 binds the farnesylated PDE6a subunit through direct interaction with the farnesyl moiety, mutations compromising the integrity of the C-terminal TPR domain of AIPL1 also failed to modulate PDE6 activity efficiently. These AIPL1 variants moreover failed to promote the HSP90-dependent stabilization of the PDE6a subunit in the cytosol. In summary, we have successfully vali- dated the disease-causing status of the AIPL1 variations in vitro. Our findings provide insight into the mechanism underlying the co-chaperone role of AIPL1 and will be critical for ensuring an early and effective diagnosis of AIPL1 LCA patients.
History
Publication status
- Published
File Version
- Published version
Journal
Human Molecular GeneticsISSN
0964-6906Publisher
Oxford University PressExternal DOI
Issue
22Volume
26Page range
4465-4480Department affiliated with
- Biochemistry Publications
Research groups affiliated with
- Genome Damage and Stability Centre Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2017-10-13First Open Access (FOA) Date
2017-10-13First Compliant Deposit (FCD) Date
2017-10-13Usage metrics
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