A mechanism of membrane neutral lipid acquisition by the microsomal triglyceride transfer protein.
The microsomal triglyceride transfer protein (MTP) and apolipoprotein B (apoB) belong to the vitellogenin (VTG) family of lipid transfer proteins. MTP is essential for the intracellular assembly and secretion of apoB-containing lipoproteins, the key intravascular lipid transport proteins in vertebrates. We report the predicted three-dimensional structure of the C-terminal lipid binding cavity of MTP, modeled on the crystal structure of the lamprey VTG gene product, lipovitellin. The cavity in MTP resembles those found in the intracellular lipid-binding proteins and bactericidal/permeability-increasing protein. Two conserved helices, designated A and B, at the entrance to the MTP cavity mediate lipid acquisition and binding. Helix A (amino acids 725-736) interacts with membranes in a manner similar to viral fusion peptides. Mutation of helix A blocks the interaction of MTP with phospholipid vesicles containing triglyceride and impairs triglyceride binding. Mutations of helix B (amino acids 781-786) and of N780Y, which causes abetalipoproteinemia, have no impact on the interaction of MTP with phospholipid vesicles but impair triglyceride binding. We propose that insertion of helix A into lipid membranes is necessary for the acquisition of neutral lipids and that helix B is required for their transfer to the lipid binding cavity of MTP.
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Molecular Medicine Group, MRC Clinical Sciences Centre, and National Heart and Lung Institute, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 ONN, United Kingdom.
Anderson
T A
TA
Ritchie
P J
PJ
Vanloo
B
B
Amey
J
J
Levitt
D
D
Rosseneu
M
M
Scott
J
J
Shoulders
C C
CC
D000595:Amino Acid Sequence; D001055:Apolipoproteins B / Q000737:chemistry; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002914:Chylomicrons / Q000378:metabolism; D003198:Computer Simulation; D004527:Egg Proteins; D015387:Egg Proteins, Dietary; D008051:Lipid Bilayers / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010743:Phospholipids / Q000378:metabolism; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014819:Vitellogenins / Q000737:chemistry
D001055:Apolipoproteins B; D002352:Carrier Proteins; D002914:Chylomicrons; D004527:Egg Proteins; D015387:Egg Proteins, Dietary; D008051:Lipid Bilayers; D008079:Lipoproteins, VLDL; D008563:Membrane Lipids; D010743:Phospholipids; D014819:Vitellogenins; C106092:microsomal triglyceride transfer protein; C001549:lipovitellin; D019704:Protein Disulfide-Isomerases