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

Journal of Lipid Research
H LedmyrE Ehrenborg

Abstract

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 ...Continue Reading

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Citations

Apr 24, 2012·Journal of Tropical Medicine·Rodrigo Gurgel-GonçalvesA Townsend Peterson
Jun 24, 2009·Journal of Lipid Research·Anna AminoffEwa Ehrenborg
Jan 18, 2007·Expert Opinion on Therapeutic Targets·John R Burnett, Gerald F Watts
Mar 4, 2009·Annals of Human Biology·K E LuévanoM T Magaña
May 1, 2007·Biochemistry and Molecular Biology Education : a Bimonthly Publication of the International Union of Biochemistry and Molecular Biology·Annelie BraunerEwa Ehrenborg
Jun 7, 2013·Liver International : Official Journal of the International Association for the Study of the Liver·Xian E PengXu Lin
Oct 4, 2016·Critical Reviews in Clinical Laboratory Sciences·Meghan T Walsh, M Mahmood Hussain
Jul 29, 2020·Saudi Journal of Gastroenterology : Official Journal of the Saudi Gastroenterology Association·Jie TanYongning Xin
May 14, 2016·Journal of Atherosclerosis and Thrombosis·Genovefa D KolovouGerald F Watts

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