The integrity and organization of the human AIPL1 functional domains is critical for its role as a HSP90-dependent co-chaperone for rod PDE6

Sacristan-Reviriego, Almudena, Bellingham, James, Prodromou, Chrisostomos, Kumaran, Neruban, Bainbridge, James, Michaelides, Michel and van der Spuy, Jacqueline (2017) The integrity and organization of the human AIPL1 functional domains is critical for its role as a HSP90-dependent co-chaperone for rod PDE6. Human Molecular Genetics, 26 (22). pp. 4465-4480. ISSN 0964-6906

[img] PDF - Published Version
Available under License Creative Commons Attribution-Non-Commercial.

Download (1MB)


Biallelic 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.

Item Type: Article
Keywords: AIPL1, Hsp90
Schools and Departments: School of Life Sciences > Biochemistry
Research Centres and Groups: Genome Damage and Stability Centre
Subjects: Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics
Q Science > QP Physiology > QP0501 Animal biochemistry
R Medicine > RB Pathology > RB151 Theories of disease. Etiology. Pathogenesis > RB155.5 Genetic disorders. Human chromosome abnormalities
Related URLs:
Depositing User: Chrisostomos Prodromou
Date Deposited: 13 Oct 2017 11:11
Last Modified: 20 Nov 2018 14:24

View download statistics for this item

📧 Request an update