The liganding of glycolipid transfer protein is controlled by glycolipid acyl structure

PLoS Biol. 2006 Nov;4(11):e362. doi: 10.1371/journal.pbio.0040362.

Abstract

Glycosphingolipids (GSLs) play major roles in cellular growth and development. Mammalian glycolipid transfer proteins (GLTPs) are potential regulators of cell processes mediated by GSLs and display a unique architecture among lipid binding/transfer proteins. The GLTP fold represents a novel membrane targeting/interaction domain among peripheral proteins. Here we report crystal structures of human GLTP bound to GSLs of diverse acyl chain length, unsaturation, and sugar composition. Structural comparisons show a highly conserved anchoring of galactosyl- and lactosyl-amide headgroups by the GLTP recognition center. By contrast, acyl chain chemical structure and occupancy of the hydrophobic tunnel dictate partitioning between sphingosine-in and newly-observed sphingosine-out ligand-binding modes. The structural insights, combined with computed interaction propensity distributions, suggest a concerted sequence of events mediated by GLTP conformational changes during GSL transfer to and/or from membranes, as well as during GSL presentation and/or transfer to other proteins.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Binding Sites
  • Carrier Proteins / chemistry*
  • Carrier Proteins / metabolism
  • Crystallography, X-Ray
  • Glycolipids / chemistry*
  • Glycolipids / metabolism
  • Humans
  • Ligands
  • Models, Chemical
  • Molecular Sequence Data
  • Protein Structure, Secondary
  • Sphingosine / chemistry
  • Sphingosine / metabolism
  • Structure-Activity Relationship

Substances

  • Carrier Proteins
  • Glycolipids
  • Ligands
  • lipid transfer protein
  • Sphingosine

Associated data

  • GENBANK/AF209704
  • GENBANK/AY372530
  • GENBANK/AY372531
  • GENBANK/AY372532
  • PDB/1SWX
  • PDB/1SX6
  • PDB/2EUK
  • PDB/2EUM
  • PDB/2EVD
  • PDB/2EVL
  • PDB/2EVS
  • PDB/2EVT