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PMID:21795536

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Citation

Ranganathan, S, Noyes, NC, Migliorini, M, Winkles, JA, Battey, FD, Hyman, BT, Smith, E, Yepes, M, Mikhailenko, I and Strickland, DK (2011) LRAD3, a novel low-density lipoprotein receptor family member that modulates amyloid precursor protein trafficking. J. Neurosci. 31:10836-46

Abstract

We have identified a novel low-density lipoprotein (LDL) receptor family member, termed LDL receptor class A domain containing 3 (LRAD3), which is expressed in neurons. The LRAD3 gene encodes an ∼50 kDa type I transmembrane receptor with an ectodomain containing three LDLa repeats, a transmembrane domain, and a cytoplasmic domain containing a conserved dileucine internalization motif and two polyproline motifs with potential to interact with WW-domain-containing proteins. Immunohistochemical analysis of mouse brain reveals LRAD3 expression in the cortex and hippocampus. In the mouse hippocampal-derived cell line HT22, LRAD3 partially colocalizes with amyloid precursor protein (APP) and interacts with APP as revealed by coimmunoprecipitation experiments. To identify the portion of APP that interacts with LRAD3, we used solid-phase binding assays that demonstrated that LRAD3 failed to bind to a soluble APP fragment (sAPPα) released after α-secretase cleavage. In contrast, C99, the β-secretase product that remains cell associated, coprecipitated with LRAD3, confirming that regions within this portion of APP are important for associating with LRAD3. The association of LRAD3 with APP increases the amyloidogenic pathway of APP processing, resulting in a decrease in sAPPα production and increased Aβ peptide production. Pulse-chase experiments confirm that LRAD3 expression significantly decreases the cellular half-life of mature APP. These results reveal that LRAD3 influences APP processing and raises the possibility that LRAD3 alters APP function in neurons, including its downstream signaling.

Links

PubMed PMC3189500 Online version:10.1523/JNEUROSCI.5065-10.2011

Keywords

Amyloid beta-Peptides/genetics; Amyloid beta-Peptides/metabolism; Amyloid beta-Protein Precursor/genetics; Amyloid beta-Protein Precursor/metabolism; Animals; Cells, Cultured; Cercopithecus aethiops; Cerebral Cortex/cytology; Cricetinae; Embryo, Mammalian; Endocytosis/genetics; Enzyme-Linked Immunosorbent Assay/methods; Humans; Immunoprecipitation/methods; Mice; Molecular Weight; Neurons/metabolism; Protein Binding/genetics; Protein Transport/genetics; Protein Transport/physiology; RNA, Messenger/metabolism; Receptors, LDL/genetics; Receptors, LDL/metabolism; Sequence Analysis, Protein; Transfection/methods

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:LRAD3

located_in

GO:0016020: membrane

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:16894)

Seeded From UniProt

complete

MOUSE:LRAD3

acts_upstream_of_or_within

GO:0006898: receptor-mediated endocytosis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LRAD3

enables

GO:0001540: amyloid-beta binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:LRAD3

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000117)
  • part_of:(EMAPA:17544)

Seeded From UniProt

complete

MOUSE:LRAD3

acts_upstream_of_or_within

GO:0070613: regulation of protein processing

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:A4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:A2AR95

F

Seeded From UniProt

complete

MOUSE:LRP1

acts_upstream_of_or_within

GO:0006898: receptor-mediated endocytosis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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