Low Density Receptor-Related Protein 1 Interactions With the Extracellular Matrix: More Than Meets the Eye

Abstract

The extracellular matrix (ECM) is a biological substrate composed of collagens, proteoglycans and glycoproteins that ensures proper cell migration and adhesion and keeps the cell architecture intact. The regulation of the ECM composition is a vital process strictly controlled by, among others, proteases, growth factors and adhesion receptors. As it appears, ECM remodeling is also essential for proper neuronal and glial development and the establishment of adequate synaptic signaling. Hence, disturbances in ECM functioning are often present in neurodegenerative diseases like Alzheimer’s disease. Moreover, mutations in ECM molecules are found in some forms of epilepsy and malfunctioning of ECM-related genes and pathways can be seen in, for example, cancer or ischemic injury. Low density lipoprotein receptor-related protein 1 (Lrp1) is a member of the low density lipoprotein receptor family. Lrp1 is involved not only in ligand uptake, receptor mediated endocytosis and lipoprotein transport—functions shared by low density lipoprotein receptor family members—but also regulates cell surface protease activity, controls cellular entry and binding of toxins and viruses, protects against atherosclerosis and acts on many cell signaling pathways. Given the plethora of functions, it is not surprising that Lrp1 also impacts the ECM and is involved in its remodeling. This review focuses on the role of Lrp1 and some of its major ligands on ECM function. Specifically, interactions with two Lrp1 ligands, integrins and tissue plasminogen activator are described in more detail.

Low Density Lipoprotein Receptor-Related Protein-1 (LRP1) Is Involved in the Uptake of Clostridioides difficile Toxin A and Serves as an Internalizing Receptor

“…We here show that TcdA bound to LRP1 cluster II and IV ( Figure 4C). This is consistent with the notion that most LRP1 ligands bind to cluster II and IV (Bres and Faissner, 2019). Furthermore, the related TpeL has been shown to bind to cluster IV as well (Schorch et al, 2014).…”

“…Many LRP1 ligands bind to LRP1 cluster II and IV (Bres and Faissner, 2019). To evaluate if TcdA binds to LRP1 cluster II and IV, TcdA binding to LRP1 cluster II (covering amino acids 786 to 1,165) and IV (covering amino acids 3332 to 3779) immobilized on nitrocellulose was detected by Western blot analysis using polyclonal antitoxin antibodies.…”

“…The a chain consists of ligand-binding-type repeats forming 4 clusters that are separated by epidermal growth factor repeats and allow interaction with diverse molecules. LRP1 ligands (including apolipoprotein E, Lipoprotein lipase, coagulation factor VIII light chain, Lactoferrin, plasminogen activator inhibitor (PAI), and tissue plasminogen activator (tPA)) bind to clusters II and IV (Lillis et al, 2008;Herz et al, 2009;Bres and Faissner, 2019).…”

Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Is a Negative Regulator of Oligodendrocyte Progenitor Cell Differentiation in the Adult Mouse Brain

“…LRP1, also known as CD91 or the α2 macroglobulin (α2M) receptor, is highly expressed by OPCs and is rapidly downregulated during OL differentiation (Auderset et al, 2016a). This large cell surface receptor, comprising a 515 kDa extracellular α-chain and an 85 kDa β-chain, could influence OPC behavior in a number of ways, as it interacts with a large variety of ligands, as well as extracellular and intracellular proteins, to facilitate signal transduction (Auderset et al, 2016b;Bres and Faissner, 2019). In other cell types, LRP1 acts as a receptor or co-receptor to initiate intracellular signal transduction, but also facilitates ligand endocytosis, transcytosis, or processing (Cam et al, 2005;Parkyn et al, 2008;Su et al, 2008;Yamamoto et al, 2014;Liu et al, 2017;Van Gool et al, 2019;Rauch et al, 2020), as well as receptor, channel and transporter trafficking (Parkyn et al, 2008;Maier et al, 2013;Nakajima et al, 2013;Liu et al, 2015;Boyé et al, 2017;Kadurin et al, 2017;Wujak et al, 2018) to influence blood brain barrier permeability (Polavarapu et al, 2007), lipid metabolism, glucose homeostasis, neuroinflammation (Brifault et al, 2017(Brifault et al, , 2019; Actis Dato and Chiabrando, 2018) and synaptic plasticity (Zhuo et al, 2000).…”

Conditional Deletion of LRP1 Leads to Progressive Loss of Recombined NG2-Expressing Oligodendrocyte Precursor Cells in a Novel Mouse Model

“…It consists of two covalently bound subunits, an 85 kDa intracellular α-chain and 515 kDa extracellular β-chain [1]. As a multifunctional receptor, LRP1 can bind a variety of up to 40 different ligands such as apolipoproteins (Apo), extracellular matrix molecules, and growth factors and is involved in their endocytosis [1,2]. Apolipoproteins, especially ApoE, mediate cholesterol transport in various cell types [3].…”