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CD91, low density lipoprotein (LDL) receptor related protein (LRP) 1, apolipoprotein E [apoE] receptor 1, chylomicron remnant receptor or alpha-2 macroglobulin receptor

Function: - endocytic receptor involved in endocytosis & in phagocytosis of apoptotic cells - required for early embryonic development - involved in cellular lipid homeostasis - involved in plasma clearance of chylomicron remnants & activated LRPAP1 (alpha 2-macroglobulin), as well as the local metabolism of complexes between plasminogen activators & their endogenous inhibitors - may modulate cellular events, such as APP metabolism, kinase-dependent intracellular signaling, neuronal Ca+2 signaling as well as neurotransmission - intracellular domain interacts with MAFB (putative) - found in a complex with PID1/PCLI1, LRP1 & CUBNI - interacts with SNX17, PID1/PCLI1, PDGF & CUBN - the intracellular domain interacts with SHC1, GULP1 & DAB1 - interacts with LRPAP1 - gamma-secretase-dependent cleavage of LRP-85 releases the intracellular domain from the membrane - phosphorylated on Ser & Thr - phosphorylated on Tyr upon stimulation with PDGF - Tyr phosphorylation promotes interaction with SHC1 - LRP1 binds 30 different ligands, including: a) apo E b) alpha-2 macroglobulin c) tissue plasminogen-activator (tPA) d) tPA/plasminogen-activator inhibitor-1 complex (PAI-1) e) prourokinase & urokinase (PAI-1) f) TFPI g) lactoferrin h) lipoprotein lipase i) factor VIII j) protease nexin-2 [10] k) heat shock proteins l) amyloid-beta peptide (a-beta) [12] - LRP1 associates with cell-surface proteoglycan, which serves to non-specifically bind proteins & present them for specific binding to the receptor LRP1 - LRP1 associates with p39RAP that modifies binding of ligands to the LRP1-alpha - LRP1 binds ApoE* - LRP also binds & internalizes the protease/protease-inhibitor complex of alpha-2 macroglobulin - the receptor alpha-2 macroglobulin complex may be involved in clearance of proteases & other proteins Structure: - heterodimer of an 85-kD membrane-bound carboxyl subunit & a non-covalently attached 515-kD amino-terminal subunit derived from a 4544 amino acid precursor (see LRP1 precursor) - contains 31 complement repeats & 22 growth factor repeats - the N-terminus is blocked - homologous to the LDL receptor Compartment: - cell membrane, coated pit - after cleavage, the intracellular domain (LRPICD) is detected both in the cytoplasm & in the nucleus Expression: - most abundant in liver, brain & lung - highest expression of LRP1 is in liver - expressed in brain - expressed on brain capillaries - binding of alpha-2 macroglobulin associated with Ca+2 influx through the NMDA receptor - lung - fibroblasts - dendritic cells - macrophages Pathology: - hepatic LRP1 binds apo E3 & apo E4, but not apo E2; [8] thus homozygous apo E2 is associated with dysbetalipoproteinemia (Frederickson type 3 hyperlipoproteinemia)

Interactions

molecular events

Related

alpha-2-macroglobulin receptor-associated protein; alpha-2-MRAP; low density lipoprotein receptor-related protein-associated protein 1; RAP; p39RAP (LRPAP1, A2MRAP) alpha-2-macroglobulin; alpha-2-M; C3 & PZP-like alpha-2-macroglobulin domain-containing protein 5 (A2M, CPAMD5, FWP007) apolipoprotein E (APOE) chylomicron hyperlipoproteinemia type 3; familial dysbetalipoproteinemia; remnant hyperlipidemia; remnant hyperlipoproteinaemia; broad beta disease; remnant removal disease intermediate density lipoprotein (IDL) or VLDL remnant low density lipoprotein (LDL) receptor related protein (LRP) 2 (LRP2, glycoprotein 330, gp330) low-density lipoprotein receptor; LDL receptor; apoB/E receptor (LDLR) LRP1 gene or apoE receptor gene or alpha-2 macroglbulin receptor gene proteoglycan

General

cluster-of-differentiation antigen; cluster designation antigen; CD antigen low-density lipoprotein (LDL) receptor related protein (LRP) multisubunit protein

Properties

COMPARTMENT: plasma membrane SUBUNITS: LRP1 alpha MOTIF: YWTD {N-terminal} cysteine-rich region MOTIF: binding site FOR-BINDING-OF: alpha-2-macroglobulin :STATE active state binding site FOR-BINDING-OF: apolipoprotein E binding site FOR-BINDING-OF: plasminogen activator inhibitor 1 :MOTIF binding site :FOR_BINDING_OF urokinase :EFFECTOR_BOUND UROKINASE Ca+2-binding site binding site FOR-BINDING-OF: alpha-2-macroglobulin receptor-associated protein EGF domain domain HOMOLOGY: complement YWTD (4) cysteine-rich region MOTIF: binding site FOR-BINDING-OF: apolipoprotein E EGF domain YWTD cysteine-rich region MOTIF: binding site FOR-BINDING-OF: apolipoprotein E Ca+2-binding site binding site FOR-BINDING-OF: alpha-2-macroglobulin receptor-associated protein EGF domain domain HOMOLOGY: complement YWTD {perimembrane} binding site SITE: ALPHA1 EFFECTOR-BOUND: beta BOUND-VIA: binding site LRP1-beta MOTIF: binding site SITE: BETA1 EFFECTOR-BOUND: alpha BOUND-VIA: binding site transmembrane domain NPXY motif NAME: NPXY motif (2) GENE: LRP1 gene

Database Correlations

OMIM 107770 UniProt Q07954 Entrez Gene 4035

References

  1. Primary Hyperlipoproteinemias, Steiner & Shafrir (eds), McGraw Hill, NY, 1991, pg 32
  2. Beisiegel et al Nature 341(6238):162-4, 1989
  3. Descamps et al J Biol Chem 268(2):974-81, 1993
  4. Wolf et al Am J Pathol 141:37 1992
  5. Williams et al J Biol Chem 267:9035 1992
  6. Herz et al EMBO J 7:4199 1988
  7. Strickland et al J Biol Chem 265:17401 1990
  8. Tietz Textbook of Clinical Chemistry, 2nd ed. Burtis CA & Ashwood ER (eds), WB Saunders Co, Philadelphia PA, 1993, pg 1025
  9. Herz & Strickland J Cin Invest 108:779, 2001
  10. Rebeck et al Molecular Brain Res 87: 238, 2001
  11. http://www.pathologyoutlines.com/cdmarkers.html 4 May 2004
  12. Sagare A et al, Clearance of amyloid-beta by circulating lipoprotein receptors Nat Med 2007, 13:1029 PMID: 17694066

Component-of

molecular complex

Components

LDL receptor-related protein (LRP) 1-alpha LDL receptor-related protein (LRP) 1-beta