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PMID:17452316

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Citation

Zhang, DW, Lagace, TA, Garuti, R, Zhao, Z, McDonald, M, Horton, JD, Cohen, JC and Hobbs, HH (2007) Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J. Biol. Chem. 282:18602-12

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degradation of hepatic low density lipoprotein receptors (LDLR), the major route of clearance of circulating cholesterol. Gain-of-function mutations in PCSK9 cause hypercholesterolemia and premature atherosclerosis, whereas loss-of-function mutations result in hypocholesterolemia and protection from heart disease. Recombinant human PCSK9 binds the LDLR on the surface of cultured hepatocytes and promotes degradation of the receptor after internalization. Here we localized the site of binding of PCSK9 within the extracellular domain of the LDLR and determined the fate of the receptor after PCSK9 binding. Recombinant human PCSK9 interacted in a sequence-specific manner with the first epidermal growth factor-like repeat (EGF-A) in the EGF homology domain of the human LDLR. Similar binding specificity was observed between PCSK9 and purified EGF-A. Binding to EGF-A was calcium-dependent and increased dramatically with reduction in pH from 7 to 5.2. The addition of PCSK9, but not heat-inactivated PCSK9, to the medium of cultured hepatocytes resulted in redistribution of the receptor from the plasma membrane to lysosomes. These data are consistent with a model in which PCSK9 binding to EGF-A interferes with an acid-dependent conformational change required for receptor recycling. As a consequence, the LDLR is rerouted from the endosome to the lysosome where it is degraded.

Links

PubMed Online version:10.1074/jbc.M702027200

Keywords

Amino Acid Sequence; Animals; COS Cells; Cells, Cultured/metabolism; Cercopithecus aethiops; Epidermal Growth Factor/metabolism; Hepatocytes/metabolism; Humans; Lysosomes/metabolism; Molecular Sequence Data; Protein Binding; Protein Conformation; Receptors, LDL/metabolism; Recombinant Proteins/chemistry; Serine Endopeptidases/chemistry; Serine Endopeptidases/physiology; Subtilisin/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:LDLR

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8NBP7

F

Seeded From UniProt

complete

HUMAN:PCSK9

involved_in

GO:0001920: negative regulation of receptor recycling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PCSK9

involved_in

GO:0007041: lysosomal transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PCSK9

enables

GO:0050750: low-density lipoprotein particle receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P01130

F

Seeded From UniProt

complete


See also

References

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