GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com

PMID:11297421

From GONUTS
Jump to: navigation, search
Citation

Koldamova, RP, Lefterov, IM, Lefterova, MI and Lazo, JS (2001) Apolipoprotein A-I directly interacts with amyloid precursor protein and inhibits A beta aggregation and toxicity. Biochemistry 40:3553-60

Abstract

Amyloid precursor protein (APP) is the source of the neurotoxic amyloid beta (Abeta) peptide associated with Alzheimer's disease. Apolipoprotein A-I (apoA-I), a constituent of high-density lipoprotein complexes, was identified by a yeast two-hybrid system as a strong and specific binding partner of full-length APP (APPfl). This association between apoA-I and APPfl was localized to the extracellular domain of APP (APPextra). Furthermore, the interaction between apoA-I and APPfl was confirmed by coprecipitation using recombinant epitope-tagged APPextra and purified apoA-I. Several functional domains have been identified in APPextra, and we focused on a possible interaction between apoA-1 and the pathologically important Abeta peptide, because APPextra contains the nontransmembrane domain of Abeta. The binding between apoA-I and Abeta was saturable (K(d) = 6 nM), specific, and reversible. APPextra also competed with apoA-I for binding to Abeta. Direct evidence for this interaction was obtained by the formation of an SDS-resistant Abeta-apoA-I complex in polyacrylamide gels. Competitive experiments with apolipoprotein E (isoforms E2 and E4) showed that apoA-I had a higher binding affinity for Abeta. We also found that apoA-I inhibited the beta-sheet formation of Abeta with a mean inhibitory concentration close to that of alpha2-macroglobulin. Finally, we demonstrated that apoA-I attenuated Abeta-induced cytotoxicity. These results suggest apoA-I binds to at least one extracellular domain of APP and has a functional role in controlling Abeta aggregation and toxicity.

Links

PubMed

Keywords

Amyloid beta-Peptides/antagonists & inhibitors; Amyloid beta-Peptides/metabolism; Amyloid beta-Peptides/toxicity; Amyloid beta-Protein Precursor/genetics; Amyloid beta-Protein Precursor/metabolism; Animals; Apolipoprotein A-I/metabolism; Apolipoprotein A-I/pharmacology; Enzyme-Linked Immunosorbent Assay; Extracellular Space/metabolism; Humans; Mutagenesis, Site-Directed; Oxidation-Reduction; PC12 Cells/drug effects; PC12 Cells/metabolism; Protein Structure, Tertiary/genetics; Rats; Sodium Dodecyl Sulfate; Tetrazolium Salts/metabolism; Thiazoles/metabolism; Two-Hybrid System Techniques

Significance

Annotations

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

HUMAN:APOA1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P05067

F

Seeded From UniProt

complete

HUMAN:A4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P02647

F

Seeded From UniProt

complete

HUMAN:APOA1

enables

GO:0001540: amyloid-beta binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

See Help:References for how to manage references in GONUTS.