Wilson MH, Rajan S, Danoff A, White RJ, Hensley MR, Quinlivan VH, et al. (2020) A point mutation decouples the lipid transfer activities of microsomal triglyceride transfer protein. PLoS Genet 16(8): e1008941. https://doi.org/10.1371/journal.pgen.1008941
A point mutation decouples the lipid transfer activities of microsomal triglyceride transfer protein
|Author:||Wilson, Meredith H.1; Rajan, Sujith2; Danoff, Aidan1,3;|
1Department of Embryology, Carnegie Institution for Science, Baltimore, Maryland, United States of America
2New York University Long Island School of Medicine, Mineola, New York, United States of America
3Department of Biology, Johns Hopkins University, Baltimore, Maryland, United States of America
4Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom
5Cambridge Institute of Therapeutic Immunology & Infectious Disease, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
6Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
|Online Access:||PDF Full Text (PDF, 5.2 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2020120299019
Public Library of Science,
|Publish Date:|| 2020-12-02
Apolipoprotein B-containing lipoproteins (B-lps) are essential for the transport of hydrophobic dietary and endogenous lipids through the circulation in vertebrates. Zebrafish embryos produce large numbers of B-lps in the yolk syncytial layer (YSL) to move lipids from yolk to growing tissues. Disruptions in B-lp production perturb yolk morphology, readily allowing for visual identification of mutants with altered B-lp metabolism. Here we report the discovery of a missense mutation in microsomal triglyceride transfer protein (Mtp), a protein that is essential for B-lp production. This mutation of a conserved glycine residue to valine (zebrafish G863V, human G865V) reduces B-lp production and results in yolk opacity due to aberrant accumulation of cytoplasmic lipid droplets in the YSL. However, this phenotype is milder than that of the previously reported L475P stalactite (stl) mutation. MTP transfers lipids, including triglycerides and phospholipids, to apolipoprotein B in the ER for B-lp assembly. In vitro lipid transfer assays reveal that while both MTP mutations eliminate triglyceride transfer activity, the G863V mutant protein unexpectedly retains ~80% of phospholipid transfer activity. This residual phospholipid transfer activity of the G863V mttp mutant protein is sufficient to support the secretion of small B-lps, which prevents intestinal fat malabsorption and growth defects observed in the mttpstl/stl mutant zebrafish. Modeling based on the recent crystal structure of the heterodimeric human MTP complex suggests the G865V mutation may block triglyceride entry into the lipid-binding cavity. Together, these data argue that selective inhibition of MTP triglyceride transfer activity may be a feasible therapeutic approach to treat dyslipidemia and provide structural insight for drug design. These data also highlight the power of yolk transport studies to identify proteins critical for B-lp biology.
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
This work was supported by National Institutes of Health grants R01 DK093399 (Farber, PI; Busch-Nentwich, Co-PI), R01 GM63904 (The Zebrafish Functional Genomics Consortium; Ekker, PI, Farber, Co-PI), HL-137202 (Hussain, PI), R01 DK121490 (Hussain, PI), R01 HD094778 (Hussain, PI), F31HL139338 to J.H.T and F32DK109592 to M.H.W. (https://www.nih.gov/), as well as G. Harold & Leila Y. Mathers Foundation (Farber, PI) (http://www.mathersfoundation.org/), VA Merit Award BX004113-01A1 (Hussain, PI) (https://www.research.va.gov/), AHA Postdoctoral Fellowship 19POST34410063 to S.R. (https://www.heart.org/), Academy of Finland 318182 (Ruddock, PI) (https://www.aka.fi/en) and the Wellcome Trust [098051 and 206194] to E. Busch-Nentwich (https://wellcome.ac.uk/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
© 2020 Wilson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.