Elements of Neural Adhesion Molecules and a Yeast Vacuolar Protein Sorting Receptor Are Present in a Novel Mammalian Low Density Lipoprotein Receptor Family Member

Abstract

Normal cell development depends to a large part on multifunctional proteins that have evolved by recombination of proven modular elements. We now have discovered and characterized in rabbit such a multi-domain protein, and classify it as novel member of the low density lipoprotein (LDL) receptor gene family. The extracellular portion of the ϳ250-kDa membrane protein, termed LR11, contains a cluster of 11 LDL receptor ligand binding repeats, a group of 5 LDL receptor "YWTD" repeats, a large hexarepeat domain of structural elements found in neural cell adhesion molecules, and a domain with similarity to a yeast receptor for vacuolar protein sorting, VPS10. The cytoplasmic domain exhibits features typical of endocytosis-competent coated-pit receptors. The mosaic, and presumably multifunctional, receptor is expressed abundantly in brain, in particular the hippocampus, dentate gyrus, and cerebral cortex, and is present at significant levels in liver, adrenal glands, and testis. Western blotting of tissues and ligand blotting of LR11-transfected cells demonstrated that the novel protein binds apolipoprotein Econtaining lipoproteins. In contrast to the LDL receptor, hepatic expression of LR11 is unaffected by hyperlipidemia. The identification of this highly conserved and superbly complex protein offers the opportunity to gain new insights into the emergence of multifunctional mosaic proteins akin to the ever expanding LDL receptor gene family.

Collagenase-3 Binds to a Specific Receptor and Requires the Low Density Lipoprotein Receptor-related Protein for Internalization

“…They recognize not only lipoproteins but also a variety of nonlipoprotein ligands, including urokinase and tissue plasminogen activator with their inhibitors and participate in different physiological processes (26,(37)(38)(39)(40)(41)(42)(43)(44)(45). Ten members of this family are known to date: the LDL receptor itself, ␣ 2 -macroglobulin receptor/low density lipoprotein receptor-related protein (␣ 2 MR/LRP), very low density lipoprotein receptor, Heymann nephritis antigen/ megalin/gp330, chicken vitellogenin receptor, Drosophila Yolkless, chicken LR8B, placental calcium sensor protein (29), the newly discovered apolipoprotein E receptor 2 (apoER2) (30), and LR11 (31). These receptors share a similar structure, with a single transmembrane domain and numerous ligand binding domains organized as cysteine-rich repeats arranged in clusters, followed by two epidermal growth factor-like repeats separated from a third one by a spacer region containing a YWTD consensus sequence and an NPXY internalization signal in the cytoplasmic domain.…”

Interaction of the Cytosolic Domains of sorLA/LR11 with the Amyloid Precursor Protein (APP) and β-Secretase β-Site APP-Cleaving Enzyme

“…sorLA is a member of a novel family of vacuolar protein sorting 10 protein (Vps10p) receptors, which contain a domain with high homology to the yeast-sorting protein Vps10p (Yamazaki et al, 1996;Jacobsen et al, 2001). The 54-residue cytoplasmatic domain is highly similar to that of the cation-independent mannose 6-phosphate receptor and is also capable of binding Golgi apparatus-localized ␥-ear-containing ARF-binding (GGA) proteins (Jacobsen et al, 2002).…”

SorLA Signaling by Regulated Intramembrane Proteolysis

“…SorLA, also called LR11, is a type I transmembrane receptor with a 56-amino acid-long cytoplasmic COOH-terminal tail strongly expressed in neurons (11)(12)(13). Its large extracellular part is composed of a VPS10 domain followed by repeats as found in the family of lipoprotein receptors and fibronectin type III domains.…”

“…In mammals, head activator mediates entry into mitosis and proliferation of neuronal and neuroendocrine precursor cells after binding to the VPS10 domain of SorLA (22). Other ligands of SorLA include lipoproteins (12), PDGF-BB (23), and GDNF (24). In accordance with the multiple ligands, SorLA also seems to be involved in several functions including protein sorting (25), lipoprotein uptake (26), smooth muscle cell migration, and the development of atherosclerosis (27), but so far no signaling cascade has been identified.…”