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:24612608

From GONUTS
Jump to: navigation, search
Citation

John, BA, Meister, M, Banning, A and Tikkanen, R (2014) Flotillins bind to the dileucine sorting motif of β-site amyloid precursor protein-cleaving enzyme 1 and influence its endosomal sorting. FEBS J. 281:2074-87

Abstract

The β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a protease that participates in the amyloidogenic cleavage of the Alzheimer amyloid precursor protein. Trafficking of BACE1 has been shown to be largely mediated by an acidic cluster dileucine motif in its cytoplasmic tail. This sorting signal functions both in endocytosis and endosomal sorting/recycling of BACE1 by providing a binding site for various sorting factors, such as the Golgi-localizing γ-ear containing ADP ribosylation factor binding (GGA) proteins that mediate BACE1 sorting within endosomes. Because flotillin-1 has been suggested to bind to BACE1 cytoplasmic tail, we analyzed the role of flotillins in BACE1 sorting. We show that flotillin-1 directly binds to the dileucine motif in the cytoplasmic tail of BACE1, whereas flotillin-2 binding is mainly mediated by its interaction with flotillin-1. Depletion of flotillins results in altered subcellular localization of BACE1 in endosomes and stabilization of BACE1 protein. Furthermore, amyloidogenic processing of Alzheimer amyloid precursor protein is increased. Flotillins compete with GGA proteins for binding to the dileucine motif in the BACE1 tail, suggesting that they play an important role in endosomal sorting of BACE1. The present study shows for the first time that flotillins are involved in endosomal sorting of BACE1. Because the endosomal localization of BACE1 affects its function as the β-secretase by increasing amyloidogenic processing of the amyloid precursor protein, flotillins may play a novel role in Alzheimer's disease. The present study is the first to show that flotillins bind to a canonical sorting signal and influence the binding of endosomal sorting factors onto cargo tails.

Links

PubMed Online version:10.1111/febs.12763

Keywords

Amyloid Precursor Protein Secretases/chemistry; Amyloid Precursor Protein Secretases/metabolism; Aspartic Acid Endopeptidases/chemistry; Aspartic Acid Endopeptidases/metabolism; Endosomes/metabolism; HeLa Cells; Humans; Immunohistochemistry; Immunoprecipitation; Membrane Proteins/chemistry; Membrane Proteins/metabolism; Protein Binding/physiology; Protein Transport/physiology

Significance

Annotations

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

HUMAN:FLOT1

involved_in

GO:0072659: protein localization to plasma membrane

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P56817)

Seeded From UniProt

complete

HUMAN:BACE1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9Z2S9

F

Seeded From UniProt

complete

HUMAN:BACE1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9Z1E1

F

Seeded From UniProt

complete

HUMAN:BACE1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O75955

F

Seeded From UniProt

complete

HUMAN:BACE1

located_in

GO:0005770: late endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BACE1

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BACE1

located_in

GO:0005771: multivesicular body

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FLOT2

involved_in

GO:0010629: negative regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P56817)

Seeded From UniProt

complete

HUMAN:FLOT2

involved_in

GO:0050821: protein stabilization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:O75955)

Seeded From UniProt

complete

HUMAN:FLOT2

involved_in

GO:0072659: protein localization to plasma membrane

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P56817)

Seeded From UniProt

complete

HUMAN:FLOT2

involved_in

GO:1902992: negative regulation of amyloid precursor protein catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:FLOT1

enables

GO:0002020: protease binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P56817

F

Seeded From UniProt

complete

RAT:FLOT2

enables

GO:0002020: protease binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P56817

F

Seeded From UniProt

complete

HUMAN:BACE1

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BACE1

part_of

GO:0005770: late endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BACE1

part_of

GO:0005771: multivesicular body

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FLOT1

involved_in

GO:0072659: protein localization to plasma membrane

ECO:0000315: mutant phenotype evidence used in manual assertion

P

has_direct_input:(UniProtKB:P56817)

Seeded From UniProt

complete

HUMAN:FLOT1

enables

GO:0002020: protease binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P56817

F

Seeded From UniProt

complete

Notes

See also

References

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