Acta Crystallographica Section D

Biological Crystallography

Volume 69, Part 4 (April 2013)

research papers

Acta Cryst. (2013). D69, 603-616    [ doi:10.1107/S0907444913000024 ]

Structural insights into lipid-dependent reversible dimerization of human GLTP

V. R. Samygina, B. Ochoa-Lizarralde, A. N. Popov, A. Cabo-Bilbao, F. Goni-de-Cerio, J. G. Molotkovsky, D. J. Patel, R. E. Brown and L. Malinina

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 [alpha]-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. [Delta]Y207 and [Delta]C-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.

PDB references: 4h2z, 4gjq, 4gxg, 4gix, 4ghs, 4gh0, 4gxd, 4gvt and 4ghp

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

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