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amyloid beta A4 protein-binding family B member 1; protein Fe65 (APBB1 FE65 RIR)
Function:
- binds to intracellular domain of APP
- Fe65 binds C-terminal region of APP
- after cleavage of APP by APP gamma secretase, carries APP C-terminus to nucleus
- Fe65 also binds to the cytolasmic domain of LRP1
- plays a central role in the response to DNA damage by translocating to the nucleus & inducing apoptosis
- may act by specifically recognizing & binding histone H2AX phosphorylated on Tyr-142 (H2AXY142ph) at DNA double-strand breaks), recruiting other pro-apoptosis factors such as MAPK8/JNK1
- required for histone H4 acetylation at DNA double-strand breaks
- ability to specifically bind modified histones & chromatin modifying enzymes such as KAT5/TIP60, probably explains its trancription activation activity
- phosphorylated following nuclear translocation
- phosphorylation at Tyr-546 enhances the transcription activation activity & reduces the affinity with RASD1/DEXRAS1
- component of a complex, at least composed of APBB1, RASD1/DEXRAS1 & APP
- interacts (via PID domain 2) with APP (with the intracellular domain of the beta-amyloid precursor protein)
- interacts (via PID domain 2) with RASD1/DEXRAS1; impairs the trancription activation activity
- interacts (via PID domain 1) with KAT5/TIP60
- interacts (via the WW domain) with the proline-rich region of APBB1IP (putative)
- interacts (via the WW domain) with histone H2AX (when phosphorylated on Tyr-142) & the proline-rich region of ENAH
- interacts with MAPK8
Structure:
- contains 2 PID domains
- contains 1 WW domain
Compartment:
- cell membrane, cytoplasm, nucleus
- in normal conditions, it mainly localizes to the cytoplasm,
- a small fraction is tethered to the cell membrane via its interaction with APP
- following exposure to DNA damaging agents, it is released from cell membrane & translocates to the nucleus
- nuclear translocation is under the regulation of APP
Alternative splicing: named isoforms=2
Expression: highly expressed in brain
Polymorphism:
- polymorphisms carry susceptibility to late onset Alzheimer's disease
Pathology:
- mutations in Fe65 affect the ability of animals to forget
Interactions
molecular events
General
amyloid beta A4 precursor protein binding family
phosphoprotein
Properties
SIZE: entity length = 710 aa
MW = 77 kD
COMPARTMENT: cytoplasm
cell nucleus
MOTIF: glutamate-rich region {158-171}
MOTIF: glutamate residue (SEVERAL)
WW domain (W/rsp5/WWP domain) {253-285}
phosphotyrosine interaction domain
NAME: phosphotyrosine interaction domain
SITE: 370-509
phosphotyrosine interaction domain
NAME: phosphotyrosine interaction domain
SITE: 542-699
MOTIF: Tyr phosphorylation site {Y546}
Database Correlations
OMIM 602709
UniProt O00213
PFAM correlations
Entrez Gene 322
Kegg hsa:322
References
- Cao X, Sudhof TC.
A transcriptionally [correction of transcriptively] active
complex of APP with Fe65 and histone acetyltransferase Tip60.
Science. 2001 Jul 6;293(5527):115-20.
Erratum in: Science 2001 Aug 24;293(5534):1436.
PMID: 11441186
- Entrez Gene :accession 322
Component-of
molecular complex