title: Receptor-associated protein facilitates proper folding and maturation of the low-density lipoprotein receptor and its class 2 mutants.
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 Ca(2+) 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 (125)I-LDL. Taken together, our results show that the folding, trafficking, and maturation of the LDLR and its class 2 mutants are promoted by RAP.
authors.affiliation: Department of Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Yonghe
authors.initials: Y
authors.lastname: Li
authors.forename: Wenyan
authors.initials: W
authors.lastname: Lu
authors.forename: Alan L
authors.initials: AL
authors.lastname: Schwartz
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003545:Cysteine / Q000378:metabolism; D005909:Glioblastoma; D006801:Humans; D026563:LDL-Receptor Related Protein-Associated Protein / Q000235:genetics / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000097:blood; D018832:Molecular Chaperones / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D016133:Polymerase Chain Reaction; D017510:Protein Folding; D011973:Receptors, LDL / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D026563:LDL-Receptor Related Protein-Associated Protein; D008077:Lipoproteins, LDL; D018832:Molecular Chaperones; D011973:Receptors, LDL; D011994:Recombinant Proteins; D003545:Cysteine