Low-density lipoprotein receptor-related protein in metalloproteinase-mediated pathologies: recent insights

Figures & data

Figure 1 The low-density lipoprotein (LDL) receptor gene family.

Notes: (A) The core of the LDL receptor family consists of the LDL receptor (LDLR), VLDL receptor (VLDLR), apolipoprotein E receptor 2 (ApoER-2), LRP-4 (multiple epidermal growth factor containing protein 7; MEGF7), LRP-1, LRP-1b, and LRP-2 (megalin). The extracellular domains consist of arrays of ligand-binding type repeats, always followed by epidermal growth factor precursor homology domains. All receptors are anchored in the plasma membrane by a single membrane-spanning segment and contain a short cytoplasmic tail. (B) Distantly related receptors LRP-5 and LRP-6, which do not contain NPxY motifs in their cytoplasmic tail, and LR11/SorLA, which harbors a VPS10 homology domain and six fibronectin repeats.
Abbreviation: VLDL, very low-density lipoprotein.

Figure 2 Different mechanisms of low-density lipoprotein receptor-related protein 1 (LRP-1)-mediated clearance of matrix metalloproteinases (MMPs).

Notes: The more straightforward mechanism is the direct association of proMMP-9 with LRP-1. ProMMP-13 first binds to an unidentified 170 kDa cell surface coreceptor before LRP-1-mediated endocytosis. LRP-1-mediated clearance of proMMP-2 involves two different coreceptors: if bound to thrombospondin (TSP), proMMP-2 first associates with an unknown cell surface heparan sulfate proteoglycan (HSPG) before interaction with LRP-1, and when complexed with TIMP-2, proMMP-2 first binds to an unidentified coreceptor.

Figure 3 Low-density receptor-related protein 1 (LRP-1) ectodomain shedding and regulated intramembrane proteolysis.

Notes: LRP-1 undergoes a cleavage by a proteolytic enzyme in the extracellular domain of its β-chain, leading to the release of its ectodomain. After this shedding, LRP-1 undergoes a γ-secretase-dependent intramembrane cleavage of the 25 kDa membrane-bound β chain, leading to the release of the intracellular domain (LRP-ICD), a fragment of approximately 12 kDa. This process, called regulated intramembrane proteolysis (RIP), may in some cases be coupled with nuclear signaling, as previously reported for Notch and amyloid precursor protein.