J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M600072-JLR200 on April 14, 2006

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Journal of Lipid Research, Vol. 47, 1378-1385, July 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

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

H. Ledmyr*, L. Ottosson{dagger}, M. Sunnerhagen§ and E. Ehrenborg1,*

* Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska University Hospital, Stockholm, Sweden
{dagger} Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
§ Department of Chemistry, Division of Molecular Biotechnology, Linköping University, Linköping, Sweden

Published, JLR Papers in Press, April 14, 2006.

1 To whom correspondence should be addressed. e-mail: ewa.ehrenborg{at}ki.se

The microsomal triglyceride transfer protein (MTTP) is essential for the assembly of VLDLs. We 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 (Ile128Thr) 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 MTTPN-Thr128 was greatly reduced, and this protein was also more extensively cleaved in limited proteolysis experiments compared with MTTPN-Ile128; both of these findings support a less compact fold. On adding LDL, which includes natively folded apolipoprotein B (apoB), decreased stability of the MTTPN-Thr128-LDL complex was observed compared with 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 reduced structural stability, leading to decreased binding of MTTP to LDL particles. Because the major MTTP binding target on LDL is apoB, the Ile128Thr polymorphism could target the MTTP-apoB interaction.

Supplementary key words missense polymorphism • protein function • limited proteolysis • circular dichroism


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