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Using Scaffold Liposomes to Reconstitute Lipid-proximal Protein-protein Interactions In Vitro
Published on: January 11, 2017
Structural insights into lipid-dependent reversible dimerization of human GLTP
Valeria R Samygina1, Borja Ochoa-Lizarralde, Alexander N Popov
1Structural Biology Unit, CIC bioGUNE, Technology Park of Bizkaia, 48160 Derio, Spain.
Summary
Human glycolipid transfer protein (hsGLTP) forms dimers to transfer glycosphingolipids (GSLs). Structural analysis reveals lipid-mediated dimerization is crucial for hsGLTP function and GSL transfer activity.
Area of Science:
- Structural biology
- Biochemistry
- Molecular biology
Background:
- Human glycolipid transfer protein (hsGLTP) exhibits broad selectivity for glycosphingolipids (GSLs).
- A specific mutation (D48V) enhances hsGLTP selectivity for sulfatides with long acyl chains.
- Lipid-mediated homodimerization is a potential functional aspect of hsGLTP.
Purpose of the Study:
- To elucidate the functional roles of lipid-mediated homodimerization in hsGLTP.
- To investigate the structural basis of enhanced sulfatide selectivity in the D48V mutant.
- To understand the role of dimerization in the conformation and activity of hsGLTP.
Main Methods:
- X-ray crystallography: Nine novel crystal structures of hsGLTP and its D48V mutant complexed with short-acyl-chain sulfatides.
- Structural analysis: Detailed examination of homodimeric structures, interfaces, and conformational differences.
- Mutagenesis: Creation and analysis of deletion mutants (ΔY207 and ΔC-end) to assess the role of the C-terminus.
Main Results:
- All hsGLTP-sulfatide complexes adopted homodimeric structures stabilized by interactions involving the lipid, C-terminus, and specific alpha-helices.
- The D48V mutant displayed a 'locked' dimer conformation, unlike the flexible 'hinge-like' conformation of wild-type hsGLTP dimers.
- Differences in dimer interfaces highlighted the importance of dimerization in positioning key residues like His140 and influencing the C-terminus conformation.
- Deletion mutants lacking or truncating the C-terminus showed a significant loss of transfer activity.
Conclusions:
- Ligand-dependent reversible dimerization is integral to the function of human glycolipid transfer protein.
- The dimeric structure, particularly the C-terminus, plays a critical role in the precise positioning of the glycolipid recognition center.
- The 'locked' dimer conformation of the D48V mutant may underlie its enhanced selectivity for specific sulfatides.
