low-density lipoprotein (LDL) receptor-related protein 8; apolipoprotein E receptor 2 (LRP8, APOER2)

Function: - cell surface receptor for Reelin (RELN) & apoE - natural isoforms of apoE (E2, E3, E4) have similar affinities for LRP8 - role in transmitting the extracellular Reelin signal to intracellular signaling processes, by binding to DAB1 on its cytoplasmic tail - Reelin acts via both the VLDL receptor (VLDLR) & LRP8 to regulate DAB1 Tyr phosphorylation & microtubule function in neurons - LRP8 has higher affinity for Reelin than VLDLR - LRP8 is a component of the Reelin pathway which governs neuronal layering of the forebrain during embryonic brain development - binds the endoplasmic reticulum resident p39RAP - binds dimers of beta 2-glycoprotein 1 & may play role in suppression of platelet aggregation in the vasculature - highly expressed in the initial segment of the epididymis, where it affects the functional expression of clusterin & phospholipid hydroperoxide glutathione peroxidase (PHGPx), two proteins required for sperm maturation - may also function as an endocytic receptor - Reelin associates with two or more receptor molecules - interacts with DAB1 & JNK-interacting proteins - interacts with SNX17 (putative) - undergoes sequential, furin & gamma-secretase dependent, proteolytic processing, resulting in the extracellular release of the entire ligand-binding domain as a soluble polypeptide & in the intracellular domain (ICD) release into the cytoplasm - the gamma-secretase-dependent proteolytical processing occurs after the bulk of the extracellular domain has been shed, in a furin- dependent manner, in alternatively spliced isoforms carrying the furin cleavage site - hypoglycosylation (mainly hypo-O-glycosylation) leads to increased extracellular cleavage, which in turn results in accelerating release of the intracellular domain by the gamma-secretase - the resulting receptor fragment is able to inhibit Reelin signaling & in particular the Reelin-induced DAB1 phosphorylation (putative) - Tyr phosphorylated upon apoE binding Structure: - O-glycosylated - some alternatively spliced isoforms lack the O-linked sugar domain (putative) - the cytoplasmic domain is involved in the binding of DAB1 & in the recruitment of JNK-interacting proteins - isoforms, which lack part of the cytoplasmic domain, are unable to recruit members of the family of JNK interacting proteins (JIP) to the cytoplasmic tail (putative) - belongs to the LDLR family - contains 2 EGF-like domains - contains 7 LDL-receptor class A domains - contains 5 LDL-receptor class B repeats Compartment: cell membrane, secreted Alternative splicing: - named isoforms=5 - additional isoforms seem to exist - insert in the extracellular part which carries a furin cleavage site - no differences observed in the pattern splicing between control & Alzheimer brains Expression: - expressed mainly in brain & placenta - expressed in cortical & cerebellar layers adjacent to layers expressing reelin - also expressed in platelets & megakaryocytic cells - not expressed in the liver Pathology: - genetic variation in LRP8 is associated with susceptibility to myocardial infarction type 1

Properties

SIZE: entity length = 963 aa MW = 106 kD COMPARTMENT: cellular membrane MOTIF: signal sequence {1-32} LDL-receptor class A {46-82} MOTIF: cysteine residue {C47} MODIFICATION: cysteine residue {C59} cysteine residue {C54} MODIFICATION: cysteine residue {C72} cysteine residue {C59} MODIFICATION: cysteine residue {C47} cysteine residue {C66} MODIFICATION: cysteine residue {C81} cysteine residue {C72} MODIFICATION: cysteine residue {C54} cysteine residue {C81} MODIFICATION: cysteine residue {C66} LDL-receptor class A {85-123} MOTIF: cysteine residue {C86} MODIFICATION: cysteine residue {C98} cysteine residue {C93} MODIFICATION: cysteine residue {C111} cysteine residue {C98} MODIFICATION: cysteine residue {C86} cysteine residue {C105} MODIFICATION: cysteine residue {C122} cysteine residue {C111} MODIFICATION: cysteine residue {C93} cysteine residue {C122} MODIFICATION: cysteine residue {C105} LDL-receptor class A {126-164} MOTIF: cysteine residue {C127} MODIFICATION: cysteine residue {C141} cysteine residue {C134} MODIFICATION: cysteine residue {C154} cysteine residue {C141} MODIFICATION: cysteine residue {C127} cysteine residue {C148} MODIFICATION: cysteine residue {C163} cysteine residue {C154} MODIFICATION: cysteine residue {C134} cysteine residue {C163} MODIFICATION: cysteine residue {C148} LDL-receptor class A {166-202} MOTIF: cysteine residue {C167} MODIFICATION: cysteine residue {C179} cysteine residue {C174} MODIFICATION: cysteine residue {C192} N-glycosylation site {N176} cysteine residue {C179} MODIFICATION: cysteine residue {C167} cysteine residue {C186} MODIFICATION: cysteine residue {C201} cysteine residue {C192} MODIFICATION: cysteine residue {C174} cysteine residue {C201} MODIFICATION: cysteine residue {C186} LDL-receptor class A {205-246} MOTIF: cysteine residue {C206} MODIFICATION: cysteine residue {C221} cysteine residue {C213} MODIFICATION: cysteine residue {C234} cysteine residue {C221} MODIFICATION: cysteine residue {C206} cysteine residue {C228} MODIFICATION: cysteine residue {C245} cysteine residue {C234} MODIFICATION: cysteine residue {C213} cysteine residue {C245} MODIFICATION: cysteine residue {C228} LDL-receptor class A {258-295} MOTIF: cysteine residue {C259} MODIFICATION: cysteine residue {C272} cysteine residue {C267} MODIFICATION: cysteine residue {C285} cysteine residue {C272} MODIFICATION: cysteine residue {C259} cysteine residue {C279} MODIFICATION: cysteine residue {C294} cysteine residue {C285} MODIFICATION: cysteine residue {C267} cysteine residue {C294} MODIFICATION: cysteine residue {C279} LDL-receptor class A {298-334} MOTIF: cysteine residue {C299} MODIFICATION: cysteine residue {C311} cysteine residue {C306} MODIFICATION: cysteine residue {C324} cysteine residue {C311} MODIFICATION: cysteine residue {C299} cysteine residue {C318} MODIFICATION: cysteine residue {C333} cysteine residue {C324} MODIFICATION: cysteine residue {C306} cysteine residue {C333} MODIFICATION: cysteine residue {C318} EGF domain {336-375} MOTIF: cysteine residue {C340} MODIFICATION: cysteine residue {C351} cysteine residue {C347} MODIFICATION: cysteine residue {C360} cysteine residue {C351} MODIFICATION: cysteine residue {C340} cysteine residue {C360} MODIFICATION: cysteine residue {C347} cysteine residue {C362} MODIFICATION: cysteine residue {C374} cysteine residue {C374} MODIFICATION: cysteine residue {C362} EGF domain {376-415} MOTIF: cysteine residue {C380} MODIFICATION: cysteine residue {C390} cysteine residue {C386} MODIFICATION: cysteine residue {C399} cysteine residue {C390} MODIFICATION: cysteine residue {C380} cysteine residue {C399} MODIFICATION: cysteine residue {C386} cysteine residue {C401} MODIFICATION: cysteine residue {C414} cysteine residue {C414} MODIFICATION: cysteine residue {C401} N-glycosylation site {N441} LDL-receptor class B {462-508} LDL-receptor class B {509-551} MOTIF: N-glycosylation site {N518} N-glycosylation site {N538} LDL-receptor class B {552-595} LDL-receptor class B {596-639} LDL-receptor class B {640-681} Clustered O-linked oligosaccharides {740-798} MOTIF: N-glycosylation site {N772} N-glycosylation site {N807} transmembrane domain {827-847}

Database Correlations

OMIM correlations MORBIDMAP 602600 UniProt Q14114 PFAM correlations Entrez Gene 7804 Kegg hsa:7804

References

UniProt :accession Q14114