J. Lipid Res.
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A more recent version of this article appeared on July 1, 2006

Papers In Press, published online ahead of print April 14, 2006
J. Lipid Res., doi:10.1194/jlr.M600072-JLR200
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Submitted on February 10, 2006
Revised on April 10, 2006
Accepted on April 13, 2006

The Ile128Thr polymorphism influences stability and ligand binding properties of the microsomal triglyceride transfer protein

Helena Ledmyr, Lars Ottosson, Maria Sunnerhagen, and Ewa Ehrenborg

Department of Medicine, Karolinska Institutet, Stockholm 171 76

Corresponding Author: ewa.ehrenborg{at}ki.se

The microsomal triglyceride transfer protein, MTTP is essential for the assembly of very-low density lipoproteins (VLDLs). We have recently observed that a polymorphism in the MTTP promoter (-493G>T), which is in allelic association with an isoleucine-to-theronine substitution at position 128 in the expressed protein, confers an increased risk of coronary heart disease. Two variant proteins comprising amino acids 16-297 of intact MTTP, MTTPN-Ile128 and MTTPN-Thr128, had similar native secondary structure content as judged by Circular Dichroism. However, the thermal stability of the MTTPN-Thr128 was greatly reduced, and was also more extensively cleaved in limited proteolysis experiments compared to MTTPN-Ile128, both of which support a less compact fold. On adding LDL, which includes natively folded apoB, decreased stability of the MTTPN-Thr128-LDL complex was observed compared to that of the MTTPN-Ile128-LDL complex. In a refined model of the N-terminal domain of MTTP, residue 128 is located in a surface-exposed position, in the same region as an identified MTTP binding site in the homologous apoB protein. Thus, the Ile128Thr polymorphism confers a reduced structural stability, leading to decreased binding of MTTP to LDL particles. Since the major MTTP binding target on LDL is apoB, the Ile128Thr polymorphism could target the MTTP-apoB interaction.


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Hepatocyte nuclear factor 1 binding element within the promoter of microsomal triglyceride transfer protein (MTTP) gene is crucial for MTTP basal expression and insulin responsiveness
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