Journal article
Interaction of Aryl Hydrocarbon Receptor-interacting Protein-like 1 with the Farnesyl Moiety
The Journal of biological chemistry, Vol.288(29), pp.21320-21328
07/19/2013
DOI: 10.1074/jbc.M113.476242
PMCID: PMC3774400
PMID: 23737531
Abstract
Background:
Mutations in AIPL1, a chaperone of the lipidated visual effector phosphodiesterase-6, cause severe childhood blindness.
Results:
AIPL1 binds the farnesyl lipid moiety. The unique insert region of AIPL1 is critical for this interaction.
Conclusion:
The AIPL1-farnesyl interaction suggests its role in the interaction with phosphodiesterase-6 and normal function of AIPL1.
Significance:
This study describes a novel mechanism of AIPL1 in retina disease.
Aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) is a photoreceptor specific chaperone of the visual effector enzyme phosphodiesterase-6 (PDE6). AIPL1 has been shown to bind the farnesylated PDE6A subunit. Mutations in AIPL1 are thought to destabilize PDE6 and thereby cause Leber congenital amaurosis type 4 (LCA4), a severe form of childhood blindness. Here, we examined the solution structure of AIPL1 by small angle x-ray scattering. A structural model of AIPL1 with the best fit to the scattering data features two independent FK506-binding protein (FKBP)-like and tetratricopeptide repeat domains. Guided by the model, we tested the hypothesis that AIPL1 directly binds the farnesyl moiety. Our studies revealed high affinity binding of the farnesylated-Cys probe to the FKBP-like domain of AIPL1, thus uncovering a novel function of this domain. Mutational analysis of the potential farnesyl-binding sites on AIPL1 identified two critical residues, Cys-89 and Leu-147, located in close proximity in the structure model. The L147A mutation and the LCA-linked C89R mutation prevented the binding of the farnesyl-Cys probe to AIPL1. Furthermore, Cys-89 and Leu-147 flank the unique insert region of AIPL1, deletion of which also abolished the farnesyl interaction. Our results suggest that the binding of PDE6A farnesyl is essential to normal function of AIPL1 and its disruption is one of the mechanisms underlying LCA.
Details
- Title: Subtitle
- Interaction of Aryl Hydrocarbon Receptor-interacting Protein-like 1 with the Farnesyl Moiety
- Creators
- Anurima Majumder - From theKota N Gopalakrishna - From thePallavi Cheguru - From theLokesh Gakhar - Department of BiochemistryNikolai O Artemyev - From the
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.288(29), pp.21320-21328
- DOI
- 10.1074/jbc.M113.476242
- PMID
- 23737531
- PMCID
- PMC3774400
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
- Grant note
- EY-10843; EY-12682 / National Institutes of Health
- Alternative title
- Farnesyl Binding by AIPL1
- Language
- English
- Date published
- 07/19/2013
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Biochemistry and Molecular Biology; Medicine Administration; Ophthalmology and Visual Sciences
- Record Identifier
- 9984025360002771
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