A single point mutation in the low-density lipoprotein receptor switches the degradation of its mature protein from the proteasome to the lysosome

The International Journal of Biochemistry & Cell Biology
José Javier Martín De LlanoErwin Knecht

Abstract

Pathogenic mutations in the low-density lipoprotein receptor prevent cholesterol uptake and cause familial hypercholesterolemia. In comparison to the biogenesis and endocytic trafficking of this receptor and some of its mutants, their degradation mechanisms are not well understood. Therefore, to gain some insights into this aspect, we analyzed the effects of proteasomal and lysosomal inhibitors on the levels of the wild type low-density lipoprotein receptor and a mutant form, C358Y, which was prevalent in a sample of Spanish familial hypercholesterolemia patients. In transfected cells, the mutant C358Y exhibited lower activity than the wild type receptor, as well as retarded post-translational processing of its precursor to the mature form. Interestingly, about 30% of the mutant precursor was degraded by a lysosomal pathway. Moreover, its mature form was more rapidly degraded than the wild type receptor (half lives of 5.3 and 10.9 h, respectively) and its degradation was exclusively dependent on a lysosomal pathway. In contrast, the mature form of the wild type receptor was mainly degraded by proteasomes and, to a minor extent (30%), by lysosomes. We conclude that a single mutation in the low-density lipoprotein receptor switch...Continue Reading

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Citations

Oct 22, 2008·Biochemical and Biophysical Research Communications·Nutjaree JeenduangSureerut Porntadavity
Aug 10, 2020·Neurochemistry International·O A Ojiakor, R J Rylett
Jun 11, 2009·Journal of Cell Science·Basil SchaheenHanna Fares
Jul 6, 2010·Clinica Chimica Acta; International Journal of Clinical Chemistry·Nutjaree JeenduangSureerut Porntadavity

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