Mechanism of LDL binding and release probed by structure-based mutagenesis of the LDL receptor

Sha Huang, Lisa Henry, Yiu Kee Ho, Henry J. Pownall, Gabrielle Rudenko

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

The LDL receptor (LDL-R) mediates cholesterol metabolism in humans by binding and internalizing cholesterol transported by LDL. Several different molecular mechanisms have been proposed for the binding of LDL to LDL-R at neutral plasma pH and for its release at acidic endosomal pH. The crystal structure of LDL-R at acidic pH shows that the receptor folds back on itself in a closed form, obscuring parts of the ligand binding domain with the epidermal growth factor (EGF)-precursor homology domain. We have used a structure-based site-directed mutagenesis approach to examine 12 residues in the extracellular domain of LDL-R for their effect on LDL binding and release. Our studies show that the interface between the ligand binding domain and the EGF-precursor homology domain seen at acidic pH buries residues mediating both LDL binding and release. Our results are consistent with an alternative model of LDL-R whereby multiple modules of the extracellular domain interact with LDL at neutral pH, concurrently positioning key residues so that at acidic pH the LDL-R:LDL interactions become unfavorable, triggering release. After LDL release, the closed form of LDL-R may target its return to the cell surface.-Huang, S., L. Henry, Y. K. Ho, H. J. Pownall, and G. Rudenko. Mechanism of LDL binding and release probed by structure-based mutagenesis of the LDL receptor.

Original languageEnglish (US)
Pages (from-to)297-308
Number of pages12
JournalJournal of Lipid Research
Volume51
Issue number2
DOIs
StatePublished - Feb 1 2010
Externally publishedYes

Fingerprint

Mutagenesis
LDL Receptors
Cholesterol
Ligands
oxidized low density lipoprotein
Site-Directed Mutagenesis
Metabolism
LDL Cholesterol
Crystal structure
Plasmas

Keywords

  • Cell surface receptor
  • Cholesterol metabolism
  • Receptor:ligand interaction

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Endocrinology

Cite this

Mechanism of LDL binding and release probed by structure-based mutagenesis of the LDL receptor. / Huang, Sha; Henry, Lisa; Ho, Yiu Kee; Pownall, Henry J.; Rudenko, Gabrielle.

In: Journal of Lipid Research, Vol. 51, No. 2, 01.02.2010, p. 297-308.

Research output: Contribution to journalArticle

Huang, Sha ; Henry, Lisa ; Ho, Yiu Kee ; Pownall, Henry J. ; Rudenko, Gabrielle. / Mechanism of LDL binding and release probed by structure-based mutagenesis of the LDL receptor. In: Journal of Lipid Research. 2010 ; Vol. 51, No. 2. pp. 297-308.
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