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Temperature-sensitive retinoid isomerase activity of RPE65 mutants associated with Leber Congenital Amaurosis.

Abstract
RPE65 is a membrane-associated retinoid isomerase involved in the visual cycle responsible for sustaining vision. Many mutations in the human RPE65 gene are associated with distinct forms of retinal degenerative diseases. The pathogenic mechanisms for most of these mutations remain poorly understood. Here, we show that three Leber congenital amaurosis -associated RPE65 mutants (R91W, Y249C and R515W) undergo rapid proteasomal degradation mediated by the 26 S proteasome non-ATPase regulatory subunit 13 (PSMD13) in cultured human retinal pigment epithelium (RPE) cells. These mutant proteins formed cytosolic inclusion bodies or high molecular weight complexes via disulfide bonds. The mutations are mapped on non-active sites but severely reduced isomerase activity of RPE65. At 30°C, however, the enzymatic function and membrane-association of the mutant RPE65s are significantly rescued possibly due to proper folding. In addition, PSMD13 displayed a drastically decreased effect on degradation of the mutant proteins in the cells grown at 30°C. These results suggest that PSMD13 plays a critical role in regulating pathogenicity of the mutations and the molecular basis for the PSMD13-mediated rapid degradation and loss of function of the mutants is misfolding of RPE65.
AuthorsSonghua Li, Jane Hu, Robin J Jin, Ashok Aiyar, Samuel G Jacobson, Dean Bok, Minghao Jin
JournalJournal of biochemistry (J Biochem) Vol. 158 Issue 2 Pg. 115-25 (Aug 2015) ISSN: 1756-2651 [Electronic] England
PMID25752820 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright© The Authors 2015. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.
Chemical References
  • Disulfides
  • Mutant Proteins
  • retinoid isomerohydrolase
  • Proteasome Endopeptidase Complex
  • 26S proteasome non-ATPase regulatory subunit 13
  • cis-trans-Isomerases
Topics
  • Cell Line
  • Cell Membrane (drug effects, metabolism)
  • Disulfides (metabolism)
  • Genetic Predisposition to Disease
  • Humans
  • Inclusion Bodies (metabolism)
  • Leber Congenital Amaurosis (enzymology, genetics)
  • Models, Molecular
  • Molecular Weight
  • Mutant Proteins (metabolism)
  • Mutation (genetics)
  • Proteasome Endopeptidase Complex (metabolism)
  • Proteolysis
  • Temperature
  • cis-trans-Isomerases (genetics)

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