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Misfolded rhodopsin mutants display variable aggregation properties.
Gragg, Megan; Park, Paul S-H.
Afiliación
  • Gragg M; Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
  • Park PS; Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: paul.park@case.edu.
Biochim Biophys Acta Mol Basis Dis ; 1864(9 Pt B): 2938-2948, 2018 09.
Article en En | MEDLINE | ID: mdl-29890221
ABSTRACT
The largest class of rhodopsin mutations causing autosomal dominant retinitis pigmentosa (adRP) is mutations that lead to misfolding and aggregation of the receptor. The misfolding mutants have been characterized biochemically, and categorized as either partial or complete misfolding mutants. This classification is incomplete and does not provide sufficient information to fully understand the disease pathogenesis and evaluate therapeutic strategies. A Förster resonance energy transfer (FRET) method was utilized to directly assess the aggregation properties of misfolding rhodopsin mutants within the cell. Partial (P23H and P267L) and complete (G188R, H211P, and P267R) misfolding mutants were characterized to reveal variability in aggregation properties. The complete misfolding mutants all behaved similarly, forming aggregates when expressed alone, minimally interacting with the wild-type receptor when coexpressed, and were unresponsive to treatment with the pharmacological chaperone 9-cis retinal. In contrast, variability was observed between the partial misfolding mutants. In the opsin form, the P23H mutant behaved similarly as the complete misfolding mutants. In contrast, the opsin form of the P267L mutant existed as both aggregates and oligomers when expressed alone and formed mostly oligomers with the wild-type receptor when coexpressed. The partial misfolding mutants both reacted similarly to the pharmacological chaperone 9-cis retinal, displaying improved folding and oligomerization when expressed alone but aggregating with wild-type receptor when coexpressed. The observed differences in aggregation properties and effect of 9-cis retinal predict different outcomes in disease pathophysiology and suggest that retinoid-based chaperones will be ineffective or even detrimental.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Rodopsina / Retinitis Pigmentosa / Pliegue de Proteína / Chaperonas Moleculares / Agregación Patológica de Proteínas Tipo de estudio: Prognostic_studies Idioma: En Revista: Biochim Biophys Acta Mol Basis Dis Año: 2018 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Rodopsina / Retinitis Pigmentosa / Pliegue de Proteína / Chaperonas Moleculares / Agregación Patológica de Proteínas Tipo de estudio: Prognostic_studies Idioma: En Revista: Biochim Biophys Acta Mol Basis Dis Año: 2018 Tipo del documento: Article