Reviewed, UniProtKB/Swiss-Prot P46933 (APBB1_RAT)

Names and origin

Protein names

Recommended name:
    Amyloid beta A4 precursor protein-binding family B member 1
Alternative name(s):
    Protein Fe65

Gene names

Name:	Apbb1
Synonyms:	Fe65

Organism

Rattus norvegicus (Rat)

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	711 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Adapter protein that forms a transcriptionally active complex with the gamma-secretase-derived amyloid precursor protein (APP) intracellular domain. Plays a central role in the response to DNA damage by translocating to the nucleus and inducing apoptosis. May act by specifically recognizing and binding histone H2AX phosphorylated on 'Tyr-142' (H2AXY142ph) at double-strand breaks (DSBs), recruiting other pro-apoptosis factors such as MAPK8/JNK1. Required for histone H4 acetylation at double-strand breaks (DSBs). Its ability to specifically bind modified histones and chromatin modifying enzymes such as KAT5/TIP60, probably explains its trancription activation activity. Ref.4 Ref.5
Subunit structure	Component of a complex, at least composed of APBB1, RASD1/DEXRAS1 and APP. Interacts (via PID domain 2) with APP (with the intracellular domain of the beta-amyloid precursor protein). Interacts (via the WW domain) with histone H2AX (when phosphorylated on 'Tyr-142'). Interacts with MAPK8. Interacts (via the WW domain) with proline-rich regions of APBB1IP and ENAH By similarity. Interacts (via PID domain 1) with KAT5/TIP60. Interacts (via PID domain 2) with RASD1/DEXRAS1; impairs the trancription activation activity. Ref.4 Ref.5
Subcellular location	Cell membrane. Cytoplasm. Nucleus. Note: In normal conditions, it mainly localizes to the cytoplasm, while 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 and translocates to the nucleus. Nuclear translocation is under the regulation of APP. Ref.4
Tissue specificity	Brain, not in liver, very low in other tissues. The long (neuron-specific) form is expressed only in brain.
Post-translational modification	Phosphorylated following nuclear translocation. Phosphorylation at Tyr-547 enhances the transcription activation activity and reduces the affinity with RASD1/DEXRAS1. Ref.4
Sequence similarities	Contains 2 PID domains. Contains 1 WW domain.
Sequence caution	The sequence CAA42999.1 differs from that shown. Reason: Frameshift at position 127.

Ontologies

Keywords
Biological process	Apoptosis DNA damage Transcription Transcription regulation
Cellular component	Cell membrane Cytoplasm Membrane Nucleus
Coding sequence diversity	Alternative splicing
Domain	Repeat
Molecular function	Chromatin regulator
PTM	Phosphoprotein
Gene Ontology (GO)
Biological process	apoptosis Inferred from electronic annotation. Source: UniProtKB-KW cell cycle arrest Inferred from sequence or structural similarity. Source: UniProtKB double-strand break repair Ref.5 Inferred from mutant phenotype. Source: UniProtKB histone H4 acetylation Ref.5 Inferred from mutant phenotype. Source: UniProtKB negative regulation of S phase of mitotic cell cycle Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of cell growth Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of thymidylate synthase biosynthetic process Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of DNA repair Ref.5 Inferred from mutant phenotype. Source: UniProtKB positive regulation of apoptosis Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of protein secretion Inferred from mutant phenotype. Source: RGD positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay. Source: RGD response to iron ion Inferred from expression pattern. Source: RGD transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	dendritic spine Inferred from direct assay. Source: RGD growth cone Inferred from sequence or structural similarity. Source: UniProtKB lamellipodium Inferred from sequence or structural similarity. Source: UniProtKB nucleus Ref.4 Ref.5 Inferred from direct assay. Source: UniProtKB perinuclear region of cytoplasm Inferred from direct assay. Source: RGD plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell postsynaptic membrane Inferred from direct assay. Source: RGD presynaptic membrane Inferred from direct assay. Source: RGD protein complex Inferred from direct assay. Source: RGD
Molecular function	beta-amyloid binding Inferred from sequence or structural similarity. Source: UniProtKB protein complex binding Inferred from physical interaction. Source: RGD transcription factor binding Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
APP	P05067	1	EBI-286177,EBI-77613	From a different organism.
App	P08592	1	EBI-286177,EBI-286155

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P46933-1)

Also known as: Long;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P46933-2)

Also known as: Short;

The sequence of this isoform differs from the canonical sequence as follows:
     463-464: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 711	711	Amyloid beta A4 precursor protein-binding family B member 1		PRO_0000076051
Regions
	Domain	254 – 286	33	WW
	Domain	365 – 533	169	PID 1
	Domain	538 – 700	163	PID 2
	Compositional bias	148 – 188	41	Glu-rich
Amino acid modifications
	Modified residue	547	1	Phosphotyrosine Ref.4
Natural variations
	Alternative sequence	463 – 464	2	Missing in isoform 2.		VSP_006798
Experimental info
	Mutagenesis	547	1	Y → F: Precules phosphorylation and increases the interaction with RASD1/DEXRAS1. Ref.4
	Mutagenesis	655	1	C → F: Abolishes interaction with APP and impairs the function in DNA repair. Ref.5
	Sequence conflict	137	1	L → K Ref.2
	Sequence conflict	150 – 154	5	EEKAA → GRRQR in CAA42999. Ref.2
	Sequence conflict	172	1	E → EEEDEEEE in CAA42999. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (Long) [UniParc]. Last modified September 27, 2004. Version 3. Checksum: A6C9820F5D2BD7BE	FASTA	711	77,656
	10 20 30 40 50 60 MSVPSSLSQS AINANSHGGP ALSFPFPLHA AHNQLLNAKL QATAVVPKDL RSAMGEGSVP 70 80 90 100 110 120 EPGPANAKWL KEGQNQLRRA ATAHRDQNRN VTLTLAEEAS QEAETAPLGP KGLMHLYSEL 130 140 150 160 170 180 ELSAHNAANR GLHGSALIIN TQGLGPDEGE EKAAGEVEEE DEDEEEEDEE EEDLSSPQGL 190 200 210 220 230 240 PEPLENVEVP SGPQVLTDGP REHSKSASLL FGMRNSAASD EDSSWATLSQ GSPSYGSPED 250 260 270 280 290 300 TDSFWNPNAF ETDSDLPAGW MRVQDTSGTY YWHIPTGTTQ WEPPGRASPS QGNSPQEESQ 310 320 330 340 350 360 LTWTGFAHQE GFEEGEFWKD EPSEEAPMEL GLKDPEEGTL PFSAQSLSPE PVPQEEENLP 370 380 390 400 410 420 QRNANPGIKC FAVRSLGWVE MTEEELAPGR SSVAVNNCIR QLSYHKNNLH DPMSGGWGEG 430 440 450 460 470 480 KDLLLQLEDE TLKLVEPQNQ TLLHAQPIVS IRVWGVGRDS GRERDFAYVA RDKLTQMLKC 490 500 510 520 530 540 HVFRCEAPAK NIATSLHEIC SKIMSERRNA RCLVNGLSLD HSKLVDVPFQ VEFPAPKNEL 550 560 570 580 590 600 VQKFQVYYLG NVPVAKPVGV DVINGALESV LSSSSREQWT PSHVSVAPAT LTILHQQTEA 610 620 630 640 650 660 VLGECRVRFL SFLAVGRDVH TFAFIMAAGP ASFCCHMFWC EPNAASLSEA VQAACMLRYQ 670 680 690 700 710 KCLDARSQTS TSCLPAPPAE SVARRVGWTV RRGVQSLWGS LKPKRLGSQT P
	Isoform 2 (Short). Checksum: 5658754E0D449B6E	FASTA	709	77,371
	10 20 30 40 50 60 MSVPSSLSQS AINANSHGGP ALSFPFPLHA AHNQLLNAKL QATAVVPKDL RSAMGEGSVP 70 80 90 100 110 120 EPGPANAKWL KEGQNQLRRA ATAHRDQNRN VTLTLAEEAS QEAETAPLGP KGLMHLYSEL 130 140 150 160 170 180 ELSAHNAANR GLHGSALIIN TQGLGPDEGE EKAAGEVEEE DEDEEEEDEE EEDLSSPQGL 190 200 210 220 230 240 PEPLENVEVP SGPQVLTDGP REHSKSASLL FGMRNSAASD EDSSWATLSQ GSPSYGSPED 250 260 270 280 290 300 TDSFWNPNAF ETDSDLPAGW MRVQDTSGTY YWHIPTGTTQ WEPPGRASPS QGNSPQEESQ 310 320 330 340 350 360 LTWTGFAHQE GFEEGEFWKD EPSEEAPMEL GLKDPEEGTL PFSAQSLSPE PVPQEEENLP 370 380 390 400 410 420 QRNANPGIKC FAVRSLGWVE MTEEELAPGR SSVAVNNCIR QLSYHKNNLH DPMSGGWGEG 430 440 450 460 470 480 KDLLLQLEDE TLKLVEPQNQ TLLHAQPIVS IRVWGVGRDS GRDFAYVARD KLTQMLKCHV 490 500 510 520 530 540 FRCEAPAKNI ATSLHEICSK IMSERRNARC LVNGLSLDHS KLVDVPFQVE FPAPKNELVQ 550 560 570 580 590 600 KFQVYYLGNV PVAKPVGVDV INGALESVLS SSSREQWTPS HVSVAPATLT ILHQQTEAVL 610 620 630 640 650 660 GECRVRFLSF LAVGRDVHTF AFIMAAGPAS FCCHMFWCEP NAASLSEAVQ AACMLRYQKC 670 680 690 700 LDARSQTSTS CLPAPPAESV ARRVGWTVRR GVQSLWGSLK PKRLGSQTP

References

[1]	"Nuclear signaling of APP cytoplasmic tail." Cao X., Suedhof T.C. Submitted (JAN-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"A rat brain mRNA encoding a transcriptional activator homologous to the DNA binding domain of retroviral integrases." Duilio A., Zambrano N., Mogavero A.R., Ammendola R., Cimino F., Russo T. Nucleic Acids Res. 19:5269-5274(1991) [PubMed: 1923810] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 121-711 (ISOFORM 2). Tissue: Brain.
[3]	"The DNA sequence encompassing the transcription start site of a TATA-less promoter contains enough information to drive neuron-specific transcription." Faraonio R., Minopoli G., Porcellini A., Costanzo F., Cimino F., Russo T. Nucleic Acids Res. 22:4876-4883(1994) [PubMed: 7800475] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 243-530. Tissue: Brain.
[4]	"Dexras1 interacts with FE65 to regulate FE65-amyloid precursor protein-dependent transcription." Lau K.-F., Chan W.-M., Perkinton M.S., Tudor E.L., Chang R.C.C., Chan H.-Y., McLoughlin D.M., Miller C.C.J. J. Biol. Chem. 283:34728-34737(2008) [PubMed: 18922798] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT TYR-547, INTERACTION WITH RASD1, MUTAGENESIS OF TYR-547.
[5]	"Fe65 is required for Tip60-directed histone H4 acetylation at DNA strand breaks." Stante M., Minopoli G., Passaro F., Raia M., Vecchio L.D., Russo T. Proc. Natl. Acad. Sci. U.S.A. 106:5093-5098(2009) [PubMed: 19282473] [Abstract] Cited for: FUNCTION, INTERACTION WITH KAT5, MUTAGENESIS OF CYS-655.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF333983 mRNA. Translation: AAK20835.1. X60469 mRNA. Translation: CAA42999.1. Frameshift. X60468 mRNA. Translation: CAA42998.1.
IPI	IPI00188409. IPI00231515.
PIR	S22571. S50818.
RefSeq	NP_536726.1.
UniGene	Rn.19953
3D structure databases
SMR	P46933. Positions 242-291, 367-506, 534-655.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-682N. DIP-852N.
IntAct	P46933. 2 interactions.
STRING	P46933.
PTM databases
PhosphoSite	P46933.
Genome annotation databases
Ensembl	ENSRNOT00000024402; ENSRNOP00000024402; ENSRNOG00000018020; Rattus norvegicus. [Genome view]
GeneID	29722.
KEGG	rno:29722.
UCSC	NM_080478. rat.
Organism-specific databases
CTD	29722.
RGD	2122. Apbb1.
Phylogenomic databases
eggNOG	roNOG12845.
HOVERGEN	P46933.
InParanoid	P46933.
PhylomeDB	P46933.
Gene expression databases
ArrayExpress	P46933.
Genevestigator	P46933.
GermOnline	ENSRNOG00000018020. Rattus norvegicus.
Family and domain databases
InterPro	IPR011993. PH_type. IPR006020. PTyr_interaction_dom. IPR001202. WW_Rsp5_WWP. [Graphical view]
Gene3D	G3DSA:2.30.29.30. PH_type. 2 hits.
Pfam	PF00640. PID. 2 hits. PF00397. WW. 1 hit. [Graphical view]
SMART	SM00462. PTB. 2 hits. SM00456. WW. 1 hit. [Graphical view]
PROSITE	PS01179. PID. 2 hits. PS01159. WW_DOMAIN_1. 1 hit. PS50020. WW_DOMAIN_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	610190.

Entry information

Entry name

APBB1_RAT

Accession

Primary (citable) accession number: P46933
Secondary accession number(s): Q99MK3

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1995
Last sequence update:	September 27, 2004
Last modified:	January 19, 2010
This is version 66 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)