Abstract
LDL receptor-related protein (LRP) is a multifunctional cell surface receptor that is expressed in many cell types. It is able to bind numerous structurally unrelated ligands. This thesis describes four novel functions of LRP in different cell types.
β2-integrins are heterodimeric proteins present at the cell surface of leukocytes. They are
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involved in various processes, like leukocyte adhesion to the vascular wall. We reported that LRP directly bound to the α-subunit of β2-integrins. Upon activation, β2-integrins form clusters in rafts of monocytes to increase the avidity for its ligands. LRP was co-immunoprecipitated with β2-integrins in the raft fraction of both naïve and stimulated monocytes. In addition, LRP colocalized with β2-integrins in the clusters. Downregulation of LRP disrupted the β2-integrin clusters, which resulted in a decreased adhesion of monocytes to activated endothelium. These data indicate that LRP is required for optimal β2-integrin function.
These results prompted us to explore the functions of LRP in other leukcoytes. Though, cellular expression patterns in lymphocytes have not been fully investigated yet. Our study showed that LRP is present in CD4+ and CD8+ T-cells, natural killer (NK) cells and B-cells. We observed a differential localization of LRP in these cells. Whereas it was present at the cell surface of NK cells and B-cells, the total LRP pool was localized intracellularly in both T-cell subtypes. In these cells, LRP could be transported to the cell surface upon a reaction with allogenic monocytes. These data point to a novel role for LRP in immunologically based diseases, like graft-versus-host-disease.
In brain, LRP is a key component in the pathogenesis of Alzheimer’s Disease (AD). It is involved in the uptake of amyloid β (Aβ) precursor protein and in the further processing of it, eventually leading to secretion of β peptides. High β concentrations can lead to the development of AD. The present study showed that β could directly bind to LRP at the cell surface brain endocthelial cells (BECs), with the Aβ40 isoform having a higher affinity than Aβ42. LRP mediated the internalization of β peptides, which were subsequently transported to the blood across the blood-brain barrier. The presence of high concentrations of Aβ decreased LRP levels in BECs, caused by a direction of LRP into the proteasomal degradation pathway. Interestingly, brain LRP levels in mice and patients suffering from AD were also decreased, suggesting LRP to be a new therapeutic target in the challenge of AD.
LRP was also involved in the binding and uptake of C4b-binding protein (C4BP), but this uptake resulted in the degradation of C4BP. Mutant C4BP with replacements of their positively charged residues were less efficiently degraded. These residues were also able to bind heparin. We found that heparan sulfate proteoglycans mediated the first step of cellular C4BP binding, which was followed by LRP-mediated degradation. C4BP can also bind anticoagulant factor protein S. Biacore experiments showed that protein S-complexed C4BP was still able to bind to LRP.
Future research may be emphasized on how one single receptor can exert many, distinct functions.
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