2. Academic Validation
  3. Pharmacological chaperone-mediated in vivo folding and stabilization of the P23H-opsin mutant associated with autosomal dominant retinitis pigmentosa

Pharmacological chaperone-mediated in vivo folding and stabilization of the P23H-opsin mutant associated with autosomal dominant retinitis pigmentosa

  • J Biol Chem. 2003 Apr 18;278(16):14442-14450. doi: 10.1074/jbc.M300087200.
Syed M Noorwez # 1,  Vladimir Kuksa # 2,  Yoshikazu Imanishi 2,  Li Zhu 2,  Sławomir Filipek 3,  Krzysztof Palczewski 2 4 5,  Shalesh Kaushal 1
Affiliations

Affiliations

  • 1 Department of Ophthalmology, University of Florida, Gainesville, Florida 55455.
  • 2 Department of Ophthalmology, University of Washington, Seattle, Washington 98195.
  • 3 International Institute of Molecular and Cell Biology and the Department of Chemistry, University of Warsaw, PL-02109 Warsaw, Poland.
  • 4 Department of Pharmacology, University of Washington, Seattle, Washington 98195.
  • 5 Department of Chemistry, University of Washington, Seattle, Washington 98195.
  • # Contributed equally.
PMID: 12566452 DOI: 10.1074/jbc.M300087200
Abstract

Protein conformational disorders, which include certain types of retinitis pigmentosa, are a set of inherited human diseases in which mutant proteins are misfolded and often aggregated. Many opsin mutants associated with retinitis pigmentosa, the most common being P23H, are misfolded and retained within the cell. Here, we describe a pharmacological chaperone, 11-cis-7-ring retinal, that quantitatively induces the in vivo folding of P23H-opsin. The rescued protein forms pigment, acquires mature glycosylation, and is transported to the cell surface. Additionally, we determined the temperature stability of the rescued protein as well as the reactivity of the retinal-opsin Schiff base to hydroxylamine. Our study unveils novel properties of P23H-opsin and its interaction with the chromophore. These properties suggest that 11-cis-7-ring retinal may be a useful therapeutic agent for the rescue of P23H-opsin and the prevention of retinal degeneration.

Figures