The LOX-1 scavenger receptor cytoplasmic domain contains a transplantable endocytic motif.
Oxidized low-density lipoprotein particles is a pro-atherogenic factor implicated in atherosclerotic plaque formation. The LOX-1 scavenger receptor binds OxLDL and is linked to atherosclerotic plaque initiation and progression. We tested the hypothesis that the LOX-1 cytoplasmic domain contains a transplantable signal for membrane protein endocytosis. Structural modeling of the LOX-1 cytoplasmic domain reveals that a tripeptide motif (DDL) implicated in LOX-1 endocytosis is part of a curved beta-pleated sheet structure. The two aspartic acid residues within this structural model are highly solvent-accessible enabling recognition by cytosolic factor(s). A triple alanine substitution of the DDL motif within the LOX-1 scavenger receptor substantially reduced endocytosis of OxLDL. Transplantation of the LOX-1 cytoplasmic domain into a transferrin receptor reporter molecule conferred efficient endocytosis on this hybrid protein. Mutation of the DDL motif within the hybrid LOX-1-TfR protein also substantially reduced receptor-mediated endocytosis. Thus a transplantable endocytic motif within the LOX-1 cytoplasmic domain is needed to ensure efficient internalization of pro-atherogenic OxLDL particles.
Endothelial Cell Biology Unit, Institute of Molecular & Cellular Biology, Leeds Institute of Genetics, Health & Therapeutics Laboratories, University of Leeds, Leeds, UK.
Ravinder S
RS
Vohra
John H
JH
Walker
Gareth J
GJ
Howell
Shervanthi
S
Homer-Vanniasinkam
Sreenivasan
S
Ponnambalam
D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D004705:Endocytosis; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary / Q000235:genetics; D051127:Scavenger Receptors, Class E / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein