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Related Experiment Videos

The LDL receptor: how acid pulls the trigger.

Natalia Beglova1, Stephen C Blacklow

  • 1Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.

Trends in Biochemical Sciences
|June 14, 2005
PubMed
Summary
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The low-density lipoprotein receptor releases bound particles in the acidic endosome via pH-induced conformational changes. This mechanism, crucial for cellular uptake, is detailed by new structural and functional studies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • The low-density lipoprotein receptor (LDLR) mediates cellular uptake of cholesterol-carrying lipoproteins.
  • Familial hypercholesterolemia is a genetic disorder caused by mutations in the LDLR, leading to high cholesterol levels.
  • The LDLR releases its ligand in the acidic environment of the endosome, but the precise mechanism remains incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanism by which the low-density lipoprotein receptor releases bound lipoprotein particles in response to endosomal acidity.
  • To integrate structural and functional data with existing knowledge of LDLR function and disease mutations.

Main Methods:

  • Analysis of recent structural and functional studies of the LDLR.

Related Experiment Videos

  • Integration of prior knowledge on normal LDLR function.
  • Consideration of disease-associated mutations causing familial hypercholesterolemia.

    • Main Results:

    • A detailed molecular model for pH-triggered lipoprotein release by the LDLR.
    • The LDLR dynamically interconverts between open (ligand-active) and closed (ligand-inactive) conformations.
    • Specific interdomain connections, both fixed and flexible, facilitate efficient ligand binding and release.

    Conclusions:

    • The acidic environment of the endosome is the trigger for lipoprotein release by the LDLR.
    • The dynamic conformational changes of the LDLR are essential for its function in lipoprotein transport.
    • Understanding this mechanism provides insights into familial hypercholesterolemia and potential therapeutic targets.