The concentration of extracellular superoxide dismutase in plasma is maintained by LRP-mediated endocytosis.
In this study, we show that human extracellular superoxide dismutase (EC-SOD) binds to low-density lipoprotein receptor-related protein (LRP). This interaction is most likely responsible for the removal of EC-SOD from the blood circulation via LRP expressed in liver tissue. The receptor recognition site was located within the extracellular matrix-binding region of EC-SOD. This region encompasses the naturally occurring Arg213Gly amino acid substitution, which affects the affinity of EC-SOD for ligands in the extracellular space. Interestingly, the binding between LRP and Arg213Gly EC-SOD was significantly reduced, thus clarifying the observation that hetero- or homozygous carriers present with a significant increase in EC-SOD in their blood. On the basis of our results, we speculate that EC-SOD synthesized locally in tissues diffuses slowly into the circulation, from where it is removed by binding to LRP present in the liver. The interaction between LRP and EC-SOD is thus likely to be important for maintaining redox balance in the circulation.
Petersen
Steen V
SV
Department of Molecular Biology, Center for Insoluble Protein Structures and Interdisciplinary Nanoscience Center, Aarhus University, DK-8000 Aarhus C, Denmark.
Thøgersen
Ida B
IB
Valnickova
Zuzana
Z
Nielsen
Morten S
MS
Petersen
Jane S
JS
Poulsen
Ebbe T
ET
Jacobsen
Christian
C
Oury
Tim D
TD
Moestrup
Søren K
SK
Crapo
James D
JD
Nielsen
Niels Chr
NC
Kristensen
Torsten
T
Enghild
Jan J
JJ
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004705:Endocytosis / Q000235:genetics / Q000502:physiology*; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008657:Metabolic Clearance Rate; D051379:Mice; D009994:Osmolar Concentration; D010084:Oxidation-Reduction; D011485:Protein Binding / Q000502:physiology; D013482:Superoxide Dismutase / Q000097:blood* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D026503:Low Density Lipoprotein Receptor-Related Protein-1; C441642:SOD3 protein, human; D013482:Superoxide Dismutase