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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, M. Sunnerhagen and E. Ehrenborg^1,*

^* Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska University Hospital, Stockholm, Sweden
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, MTTP_N-Ile128 and MTTP_N-Thr128, had similar native secondary structure content, as judged by circular dichroism. However, the thermal stability of MTTP_N-Thr128 was greatly reduced, and this protein was also more extensively cleaved in limited proteolysis experiments compared with MTTP_N-Ile128; both of these findings support a less compact fold. On adding LDL, which includes natively folded apolipoprotein B (apoB), decreased stability of the MTTP_N-Thr128-LDL complex was observed compared with that of the MTTP_N-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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