Structural Consequences of Mutations to the α‑Tocopherol Transfer Protein Associated with the Neurodegenerative Disease Ataxia with Vitamin E Deficiency

• Published in: Biochemistry (Easton) 2013-06, Vol.52 (24), p.4264-4273
• Main Authors: Bromley, Dennis, Anderson, Peter C, Daggett, Valerie
• Format: Article
• Language: English
• Subjects: Ataxia - genetics; Carrier Proteins - chemistry; Carrier Proteins - genetics; Crystallography, X-Ray; Humans; Hydrophobic and Hydrophilic Interactions; Ligands; Lipoproteins, VLDL - metabolism; Models, Genetic; Molecular Conformation; Molecular Dynamics Simulation; Mutation; Neurodegenerative Diseases - genetics; Protein Binding; Vitamin E Deficiency - genetics
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi4001084

The α-tocopherol transfer protein (α-TTP) is a liver protein that transfers α-tocopherol (vitamin E) to very-low-density lipoproteins (VLDLs). These VLDLs are then circulated throughout the body to maintain blood α-tocopherol levels. Mutations to the α-TTP gene are associated with ataxia with vitamin E deficiency, a disease characterized by peripheral nerve degeneration. In this study, molecular dynamics simulations of the E141K and R59W disease-associated mutants were performed. The mutants displayed disruptions in and around the ligand-binding pocket. Structural analysis and ligand docking to the mutant structures predicted a decreased affinity for α-tocopherol. To determine the detailed mechanism of the mutation-related changes, we developed a new tool called ContactWalker that analyzes contact differences between mutant and wild-type proteins and highlights pathways of altered contacts within the mutant proteins. Taken together, our findings are in agreement with experiment and suggest structural explanations for the weakened ability of the mutants to bind and carry α-tocopherol.