Structural insights into lipid-dependent reversible dimerization of human GLTP

Valeria R. Samygina, Borja Ochoa-Lizarralde, Alexander N. Popov, Aintzane Cabo-Bilbao, Felipe Goni-De-Cerio, Julian G. Molotkovsky, Dinshaw J. Patel, Rhoderick E. Brown, Lucy Malinina

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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 -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.

Original languageEnglish (US)
Pages (from-to)603-616
Number of pages14
JournalActa Crystallographica Section D: Biological Crystallography
Volume69
Issue number4
DOIs
StatePublished - Apr 2013

Keywords

  • GLTP fold
  • glycolipid transfer protein
  • lipid-mediated homodimerization
  • selectivity
  • sulfatides

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