Biterova, E. I., Isupov, M. N., Keegan, R. M., Lebedev, A. A., Sohail, A. A., Liaqat, I., … Ruddock, L. W. (2019). The crystal structure of human microsomal triglyceride transfer protein. Proceedings of the National Academy of Sciences, 116(35), 17251–17260. https://doi.org/10.1073/pnas.1903029116
The crystal structure of human microsomal triglyceride transfer protein
|Author:||Biterova, Ekaterina I.1,2; Isupov, Michail N.3; Keegan, Ronan M.4;|
1Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90220 Oulu, Finland
2Biocenter Oulu, University of Oulu, 90014 Oulu, Finland
3Henry Wellcome Biocatalysis Centre, Biosciences, University of Exeter, EX4 4QD Exeter, United Kingdom
4Research Complex at Harwell, Science and Technology Facilities Council Rutherford Appleton Laboratory, Didcot OX11 0FA, United Kingdom
|Online Access:||PDF Full Text (PDF, 2.5 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2019093030528
National Academy of Sciences of the United States of America,
|Publish Date:|| 2019-09-30
Microsomal triglyceride transfer protein (MTP) plays an essential role in lipid metabolism, especially in the biogenesis of very low-density lipoproteins and chylomicrons via the transfer of neutral lipids and the assembly of apoB-containing lipoproteins. Our understanding of the molecular mechanisms of MTP has been hindered by a lack of structural information of this heterodimeric complex comprising an MTPα subunit and a protein disulfide isomerase (PDI) β-subunit. The structure of MTP presented here gives important insights into the potential mechanisms of action of this essential lipid transfer molecule, structure-based rationale for previously reported disease-causing mutations, and a means for rational drug design against cardiovascular disease and obesity. In contrast to the previously reported structure of lipovitellin, which has a funnel-like lipid-binding cavity, the lipid-binding site is encompassed in a β-sandwich formed by 2 β-sheets from the C-terminal domain of MTPα. The lipid-binding cavity of MTPα is large enough to accommodate a single lipid. PDI independently has a major role in oxidative protein folding in the endoplasmic reticulum. Comparison of the mechanism of MTPα binding by PDI with previously published structures gives insights into large protein substrate binding by PDI and suggests that the previous structures of human PDI represent the “substrate-bound” and “free” states rather than differences arising from redox state.
Proceedings of the National Academy of Sciences of the United States of America
|Pages:||17251 - 17260|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
This work was supported by Academy of Finland Grants 266457 and 272573, the Sigrid Juselius Foundation, and Biocenter Oulu.
|Academy of Finland Grant Number:||
272573 (Academy of Finland Funding decision)
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