Arterioscler Thromb Vasc Biol Low-Density Lipoprotein Receptor–Related Protein-1ATVB Named Lecture Review—Insight into Author by Dudley K. Strickland, Dianaly T. Au, Patricia Cunfer, and Selen C. Muratoglu Arterioscler Thromb Vasc Biol Volume 34(3):487-498 February 19, 2014 Copyright © American Heart Association, Inc. All rights reserved.

Canonical mode of ligand binding by low-density lipo protein receptor–related protein-1 (LRP1). Canonical mode of ligand binding by low-density lipo protein receptor–related protein-1 (LRP1). A, LRP1 is synthesized as a 600-kDa protein and is cleaved by furin into a light chain (arrow) that consists of an 85-kDa subunit containing the transmembrane and intracellular domain and a noncovalently 515-kDa amino-terminal fragment. The extracellular domain contains clusters (I, II, III, and IV) of LDL receptor type A repeats to which ligands bind. The cytoplasmic tail of the receptor contains 2 NPxY motifs (*). B, Structure of the receptor associated protein D3 domain lys256 LDL receptor complex showing the calcium ion stabilizing aspartic residues 147, 149, and 151. Tryptophan 144 forms Van der wall interactions with the K256 side groups (Protein Data Bank [PDB] accession number, 2FCW). C, Structure of the apoE receptor 2 reeling complex demonstrating a similar acidic pocket for lysine 2467 on reelin (PDB accession number, 3A7Q). Dudley K. Strickland et al. Arterioscler Thromb Vasc Biol. 2014;34:487-498 Copyright © American Heart Association, Inc. All rights reserved.

Model for the role of low-density lipoprotein receptor–related protein-1 (LRP1) in the hepatic catabolism of factor VIII (fVIII). Model for the role of low-density lipoprotein receptor–related protein-1 (LRP1) in the hepatic catabolism of factor VIII (fVIII). In this model, LRP1 binds fVIII that has dissociated from von Willebrand factor (vWf). The kinetics of dissociation of fVIII from vWf has been reported60 and at 35°C occurs with a t1/2 of 100 s. Because LRP1 mediates the rapid endocytosis of ligands, this may drive the equilibrium process to generate more free fVIII. fVIII also binds to heparan sulfate proteoglycans (HSPG) on the liver surface. This binding may slightly accelerate the dissociation of vWf–fVIII complex on the cell surface although this has not been demonstrated. It has been demonstrated that 125I-labeled fVIII is selectively removed from the vWf-fVIII/complex and internalized in cells expressing LRP1, even in the presence of a large excess of vWf.49 Dudley K. Strickland et al. Arterioscler Thromb Vasc Biol. 2014;34:487-498 Copyright © American Heart Association, Inc. All rights reserved.

Genetic deletion of lrp1 from smooth muscle cells (SMCs) results in extensive disruptions in the vessel wall. Genetic deletion of lrp1 from smooth muscle cells (SMCs) results in extensive disruptions in the vessel wall. Electron microscopy images of sibling control mice expressing low-density lipoprotein receptor–related protein-1 (LRP1; A and C) and smLRP1– mice (B and D) visualizing the intact (A) vs disrupted (B) lamella (*) including the internal elastic lamina (IEL). Compare higher magnification (C) of vascular SMCs in contact with organized extracellular matrix (ECM) with collagen fiber (col) in aorta of control mice with SMCs loosely in contact with unorganized collagen in aortas from smLRP1– mice (D). Medial SMCs in control aorta are contractile with classical hill-and-valley morphology (C). SMCs from smLRP1– mice have prominent synthetic organelles (D, bracket). Proteolytic products of ECM in smLRP1– mice are cleared by phagocytosis by a macrophage (Mϕ; D; bar=2 µm for all images). Adapted with permission from Muratoglu et al.19 Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation. Dudley K. Strickland et al. Arterioscler Thromb Vasc Biol. 2014;34:487-498 Copyright © American Heart Association, Inc. All rights reserved.

Dudley K. Strickland et al. Arterioscler Thromb Vasc Biol Copyright © American Heart Association, Inc. All rights reserved.