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