A hydrophobic cluster at the surface of the human plasma phospholipid transfer protein is critical for activity on

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C Desrumaux1, C Labeur, A Verhee

  • 1Laboratory for Lipoprotein Chemistry, Faculty of Medicine, University of Ghent, B-9000 Ghent, Belgium. desrumauxcatherine@yahoo.com

The Journal of Biological Chemistry
|November 18, 2000
PubMed

Insights

Plasma phospholipid transfer protein (PLTP) uses a hydrophobic cluster to transfer phospholipids to high-density lipoprotein (HDL). This specific interaction is crucial for PLTP

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Lipid Metabolism

Background:

  • Plasma phospholipid transfer protein (PLTP) is a member of the lipid transfer/lipopolysaccharide binding protein (LT/LBP) family.
  • PLTP plays a role in lipid metabolism and lipoprotein remodeling.
  • Understanding PLTP's structure-function relationship is crucial for elucidating its biological roles.

Purpose of the Study:

  • To investigate the role of a specific hydrophobic cluster in the N-terminal region of PLTP.
  • To determine the contribution of this hydrophobic cluster to PLTP's functional activities, particularly phospholipid transfer and HDL modification.

Main Methods:

  • Construction of a three-dimensional model of PLTP based on available crystallographic data of BPI.
  • Multiple sequence alignment to identify conserved residues and structural features.
  • Engineering of single point alanine mutants (W91A, F92A, F93A) within the putative hydrophobic cluster.
  • Assay of phospholipid transfer activity from liposomes to various lipoproteins (HDL, VLDL, LDL).
  • Evaluation of HDL size conversion activity.

Main Results:

  • The PLTP model revealed a hydrophobic cluster at the N-terminal tip, substituting for charged residues involved in LPS binding in related proteins.
  • Mutants W91A, F92A, and F93A showed drastically reduced phospholipid transfer activity to HDL.
  • These mutants exhibited unchanged transfer activity towards VLDL and LDL.
  • HDL size conversion activity was significantly reduced in the mutants, correlating with the reduced transfer activity to HDL.

Conclusions:

  • A solvent-exposed hydrophobic cluster at the N-terminus of PLTP is essential for its phospholipid transfer activity specifically towards HDL.
  • This hydrophobic cluster plays a critical role in PLTP's function in HDL remodeling.
  • The findings highlight a specific structural determinant for PLTP's substrate specificity on HDL.

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