Receptor-associated protein facilitates proper folding and maturation of the low-density lipoprotein receptor and its class 2 mutants

Yonghe Li, Wenyan Lu, Alan L. Schwartz, Guojun D Bu

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Familial hypercholesterolemia is the consequence of various mutations in the low-density lipoprotein receptor (LDLR). In the current study, we show that a specialized molecular chaperone, the receptor-associated protein (RAP), promotes proper folding and subsequent exocytic trafficking of the wild-type LDLR and several of its class 2 mutants. Co-immunoprecipitation with anti-RAP antibody demonstrates that RAP interacts with the LDLR. Kinetic analyses of LDLR posttranslational folding and maturation in the absence or presence of RAP coexpression show that RAP prevents aggregation and promotes the maturation of the LDLR. Additionally, depletion of Ca2+ in intact cells impairs LDLR folding, and coexpression of RAP partially corrects this misfolding. Finally, we show that the increased mature cell surface LDLR in the presence of RAP coexpression is functional in its ability to endocytose and degrade 125I-LDL. Taken together, our results show that the folding, trafficking, and maturation of the LDLR and its class 2 mutants are promoted by RAP.

Original languageEnglish (US)
Pages (from-to)4921-4928
Number of pages8
JournalBiochemistry
Volume41
Issue number15
DOIs
StatePublished - Apr 16 2002
Externally publishedYes

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LDL Receptors
Proteins
Hyperlipoproteinemia Type II
Molecular Chaperones
Endocytosis
Immunoprecipitation
Agglomeration
Mutation
Kinetics
Antibodies

ASJC Scopus subject areas

  • Biochemistry

Cite this

Receptor-associated protein facilitates proper folding and maturation of the low-density lipoprotein receptor and its class 2 mutants. / Li, Yonghe; Lu, Wenyan; Schwartz, Alan L.; Bu, Guojun D.

In: Biochemistry, Vol. 41, No. 15, 16.04.2002, p. 4921-4928.

Research output: Contribution to journalArticle

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N2 - Familial hypercholesterolemia is the consequence of various mutations in the low-density lipoprotein receptor (LDLR). In the current study, we show that a specialized molecular chaperone, the receptor-associated protein (RAP), promotes proper folding and subsequent exocytic trafficking of the wild-type LDLR and several of its class 2 mutants. Co-immunoprecipitation with anti-RAP antibody demonstrates that RAP interacts with the LDLR. Kinetic analyses of LDLR posttranslational folding and maturation in the absence or presence of RAP coexpression show that RAP prevents aggregation and promotes the maturation of the LDLR. Additionally, depletion of Ca2+ in intact cells impairs LDLR folding, and coexpression of RAP partially corrects this misfolding. Finally, we show that the increased mature cell surface LDLR in the presence of RAP coexpression is functional in its ability to endocytose and degrade 125I-LDL. Taken together, our results show that the folding, trafficking, and maturation of the LDLR and its class 2 mutants are promoted by RAP.

AB - Familial hypercholesterolemia is the consequence of various mutations in the low-density lipoprotein receptor (LDLR). In the current study, we show that a specialized molecular chaperone, the receptor-associated protein (RAP), promotes proper folding and subsequent exocytic trafficking of the wild-type LDLR and several of its class 2 mutants. Co-immunoprecipitation with anti-RAP antibody demonstrates that RAP interacts with the LDLR. Kinetic analyses of LDLR posttranslational folding and maturation in the absence or presence of RAP coexpression show that RAP prevents aggregation and promotes the maturation of the LDLR. Additionally, depletion of Ca2+ in intact cells impairs LDLR folding, and coexpression of RAP partially corrects this misfolding. Finally, we show that the increased mature cell surface LDLR in the presence of RAP coexpression is functional in its ability to endocytose and degrade 125I-LDL. Taken together, our results show that the folding, trafficking, and maturation of the LDLR and its class 2 mutants are promoted by RAP.

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