Structural insights into lipid-dependent reversible dimerization of human GLTP

Acta Crystallogr D Biol Crystallogr. 2013 Apr;69(Pt 4):603-16. doi: 10.1107/S0907444913000024. Epub 2013 Mar 14.


Human glycolipid transfer protein (hsGLTP) forms the prototypical GLTP fold and is characterized by a broad transfer selectivity for glycosphingolipids (GSLs). The GLTP mutation D48V near the `portal entrance' of the glycolipid binding site has recently been shown to enhance selectivity for sulfatides (SFs) containing a long acyl chain. Here, nine novel crystal structures of hsGLTP and the SF-selective mutant complexed with short-acyl-chain monoSF and diSF in different crystal forms are reported in order to elucidate the potential functional roles of lipid-mediated homodimerization. In all crystal forms, the hsGLTP-SF complexes displayed homodimeric structures supported by similarly organized intermolecular interactions. The dimerization interface always involved the lipid sphingosine chain, the protein C-terminus (C-end) and α-helices 6 and 2, but the D48V mutant displayed a `locked' dimer conformation compared with the hinge-like flexibility of wild-type dimers. Differences in contact angles, areas and residues at the dimer interfaces in the `flexible' and `locked' dimers revealed a potentially important role of the dimeric structure in the C-end conformation of hsGLTP and in the precise positioning of the key residue of the glycolipid recognition centre, His140. ΔY207 and ΔC-end deletion mutants, in which the C-end is shifted or truncated, showed an almost complete loss of transfer activity. The new structural insights suggest that ligand-dependent reversible dimerization plays a role in the function of human GLTP.

Keywords: GLTP fold; glycolipid transfer protein; lipid-mediated homodimerization; selectivity; sulfatides.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / chemistry*
  • Carrier Proteins / metabolism
  • Carrier Proteins / physiology
  • Crystallography, X-Ray
  • Glycosphingolipids / chemistry
  • Glycosphingolipids / metabolism
  • Glycosphingolipids / physiology
  • Humans
  • Ligands
  • Lipid Metabolism / physiology*
  • Protein Binding
  • Protein Folding
  • Protein Multimerization / physiology*
  • Protein Structure, Secondary
  • Structure-Activity Relationship


  • Carrier Proteins
  • GLTP protein, human
  • Glycosphingolipids
  • Ligands

Associated data

  • PDB/4GH0
  • PDB/4GHP
  • PDB/4GHS
  • PDB/4GIX
  • PDB/4GJQ
  • PDB/4GVT
  • PDB/4GXD
  • PDB/4GXG
  • PDB/4H2Z