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.
journal_name
J Biochemjournal_title
Journal of biochemistryauthors
Li S,Hu J,Jin RJ,Aiyar A,Jacobson SG,Bok D,Jin Mdoi
10.1093/jb/mvv028subject
Has Abstractpub_date
2015-08-01 00:00:00pages
115-25issue
2eissn
0021-924Xissn
1756-2651pii
mvv028journal_volume
158pub_type
杂志文章abstract::A new multifunctional protein kinase, which normally exists as an inactive form in the soluble fraction in mammalian tissues, attaches to membranes to exhibit full enzymatic activity. A low concentration of Ca2+ is absolutely necessary for this activation. This process is reversible. cAMP shows no effect. The active f...
journal_title:Journal of biochemistry
pub_type: 杂志文章
doi:10.1093/oxfordjournals.jbchem.a132557
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abstract::The beta peptide (113-125), derived from a conserved sequence of the beta subunit of integrins, was synthesized to investigate its adhesive properties to matrix proteins and the effects on cell adhesion to immobilized fibronectin. In this study, we observed that the biotinylated beta peptide was able to bind efficient...
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journal_title:Journal of biochemistry
pub_type: 杂志文章
doi:10.1093/oxfordjournals.jbchem.a131809
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doi:10.1093/oxfordjournals.jbchem.a124854
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journal_title:Journal of biochemistry
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doi:10.1093/oxfordjournals.jbchem.a134462
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doi:10.1093/oxfordjournals.jbchem.a135526
更新日期:1986-03-01 00:00:00
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更新日期:2004-12-01 00:00:00
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pub_type: 杂志文章
doi:10.1093/oxfordjournals.jbchem.a134773
更新日期:1984-06-01 00:00:00
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pub_type: 杂志文章
doi:10.1093/jb/mvp053
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journal_title:Journal of biochemistry
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pub_type: 杂志文章
doi:10.1093/oxfordjournals.jbchem.a124099
更新日期:1993-06-01 00:00:00
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pub_type: 杂志文章
doi:10.1093/oxfordjournals.jbchem.a003157
更新日期:2002-05-01 00:00:00
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pub_type: 杂志文章
doi:10.1093/oxfordjournals.jbchem.a134985
更新日期:1984-11-01 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
doi:10.1093/oxfordjournals.jbchem.a123010
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journal_title:Journal of biochemistry
pub_type: 杂志文章
doi:10.1093/oxfordjournals.jbchem.a130985
更新日期:1975-11-01 00:00:00
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更新日期:1981-06-01 00:00:00