6i7s
Microsomal triglyceride transfer protein
Structural highlights
FunctionPDIA1_HUMAN This multifunctional protein catalyzes the formation, breakage and rearrangement of disulfide bonds. At the cell surface, seems to act as a reductase that cleaves disulfide bonds of proteins attached to the cell. May therefore cause structural modifications of exofacial proteins. Inside the cell, seems to form/rearrange disulfide bonds of nascent proteins. At high concentrations, functions as a chaperone that inhibits aggregation of misfolded proteins. At low concentrations, facilitates aggregation (anti-chaperone activity). May be involved with other chaperones in the structural modification of the TG precursor in hormone biogenesis. Also acts a structural subunit of various enzymes such as prolyl 4-hydroxylase and microsomal triacylglycerol transfer protein MTTP.[1] [2] Publication Abstract from PubMedMicrosomal 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 MTPalpha subunit and a protein disulfide isomerase (PDI) beta-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 beta-sandwich formed by 2 beta-sheets from the C-terminal domain of MTPalpha. The lipid-binding cavity of MTPalpha 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 MTPalpha 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. The crystal structure of human microsomal triglyceride transfer protein.,Biterova EI, Isupov MN, Keegan RM, Lebedev AA, Sohail AA, Liaqat I, Alanen HI, Ruddock LW Proc Natl Acad Sci U S A. 2019 Aug 8. pii: 1903029116. doi:, 10.1073/pnas.1903029116. PMID:31395737[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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