LAUSR

Significance This study provides a structure for microsomal triglyceride transfer protein, a key protein in lipid metabolism and transport. Microsomal triglyceride transfer protein is linked to a human disease state, abetalipoproteinemia. The structure helps us to understand how this protein functions and gives a rationale for how previously reported mutations result in loss of function of the protein and hence, cause disease. The structure also provides a means for rational drug design to treat cardiovascular disease, hypercholesterolemia, and obesity. Microsomal triglyceride transfer protein is composed of 2 subunits. The β-subunit, protein disulfide isomerase (PDI), also acts independently as a protein folding catalyst. The structure that we present here gives insights into how PDI functions in protein folding. 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.