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PMID:12805363

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Citation

Noviello, C, Vito, P, Lopez, P, Abdallah, M and D'Adamio, L (2003) Autosomal recessive hypercholesterolemia protein interacts with and regulates the cell surface level of Alzheimer's amyloid beta precursor protein. J. Biol. Chem. 278:31843-7

Abstract

The familial Alzheimer's disease gene product amyloid beta protein precursor (A beta PP) is sequentially processed by beta- and gamma-secretases to generate the A beta peptide. Although much is known about the biochemical pathway leading to A beta formation, because extracellular aggregates of A beta peptides are considered the cause of Alzheimer's disease, the biological role of A beta PP processing is only recently being investigated. Cleavage of A beta PP by gamma-secretase releases, together with A beta, a COOH-terminal A beta PP intracellular domain, termed AID. Hoping to gain clues about proteins that regulates A beta PP processing and function, we used the yeast two-hybrid system to identify proteins that interact with the AID region of A beta PP. One of the interactors isolated is the autosomal recessive hypercholesterolemia (ARH) adapter protein. This molecular interaction is confirmed in vitro and in vivo by fluorescence resonance energy transfer and in cell lysates. Moreover, we show that reduction of ARH expression by RNA interference results in increased levels of cell membrane A beta PP. These data assert a physiological role for ARH in A beta PP internalization, transport, and/or processing.

Links

PubMed Online version:10.1074/jbc.M304133200

Keywords

Amino Acid Sequence; Amyloid beta-Protein Precursor/metabolism; Base Sequence; Cell Line; Cell Membrane/metabolism; DNA Primers; Genes, Recessive; Humans; Hypercholesterolemia/metabolism; Molecular Sequence Data

Significance

Annotations

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

HUMAN:A4

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ARH

enables

GO:0001540: amyloid-beta binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P05067

F

Seeded From UniProt

complete

HUMAN:ARH

involved_in

GO:0042982: amyloid precursor protein metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ARH

involved_in

GO:1903076: regulation of protein localization to plasma membrane

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:A4

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:A4

enables

GO:0051425: PTB domain binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q5SW96

F

Seeded From UniProt

complete


See also

References

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