| Structural highlights
Function
[APBB1_HUMAN] Transcription coregulator that can have both coactivator and corepressor functions. 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. Function in association with TSHZ3, SET and HDAC factors as a transcriptional repressor, that inhibits the expression of CASP4. Associates with chromatin in a region surrounding the CASP4 transcriptional start site(s).[1] [2] [3] [4] [5]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The neuronal adaptor protein Fe65 is involved in brain development, Alzheimer disease amyloid precursor protein (APP) signaling, and proteolytic processing of APP. It contains three protein-protein interaction domains, one WW domain, and a unique tandem array of phosphotyrosine-binding (PTB) domains. The N-terminal PTB domain (Fe65-PTB1) was shown to interact with a variety of proteins, including the low density lipoprotein receptor-related protein (LRP-1), the ApoEr2 receptor, and the histone acetyltransferase Tip60. We have determined the crystal structures of human Fe65-PTB1 in its apo- and in a phosphate-bound form at 2.2 and 2.7A resolution, respectively. The overall fold shows a PTB-typical pleckstrin homology domain superfold. Although Fe65-PTB1 has been classified on an evolutionary basis as a Dab-like PTB domain, it contains attributes of other PTB domain subfamilies. The phosphotyrosine-binding pocket resembles IRS-like PTB domains, and the bound phosphate occupies the binding site of the phosphotyrosine (Tyr(P)) within the canonical NPXpY recognition motif. In addition Fe65-PTB1 contains a loop insertion between helix alpha2 and strand beta2(alpha2/beta2 loop) similar to members of the Shc-like PTB domain subfamily. The structural comparison with the Dab1-PTB domain reveals a putative phospholipid-binding site opposite the peptide binding pocket. We suggest Fe65-PTB1 to interact with its target proteins involved in translocation and signaling of APP in a phosphorylation-dependent manner.
Crystal structure of the human Fe65-PTB1 domain.,Radzimanowski J, Ravaud S, Schlesinger S, Koch J, Beyreuther K, Sinning I, Wild K J Biol Chem. 2008 Aug 22;283(34):23113-20. Epub 2008 Jun 11. PMID:18550529[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Perkinton MS, Standen CL, Lau KF, Kesavapany S, Byers HL, Ward M, McLoughlin DM, Miller CC. The c-Abl tyrosine kinase phosphorylates the Fe65 adaptor protein to stimulate Fe65/amyloid precursor protein nuclear signaling. J Biol Chem. 2004 May 21;279(21):22084-91. Epub 2004 Mar 18. PMID:15031292 doi:10.1074/jbc.M311479200
- ↑ Nakaya T, Kawai T, Suzuki T. Regulation of FE65 nuclear translocation and function by amyloid beta-protein precursor in osmotically stressed cells. J Biol Chem. 2008 Jul 4;283(27):19119-31. Epub 2008 May 9. PMID:18468999 doi:M801827200
- ↑ Lau KF, Chan WM, Perkinton MS, Tudor EL, Chang RC, Chan HY, McLoughlin DM, Miller CC. Dexras1 interacts with FE65 to regulate FE65-amyloid precursor protein-dependent transcription. J Biol Chem. 2008 Dec 12;283(50):34728-37. Epub 2008 Oct 15. PMID:18922798 doi:M801874200
- ↑ Cook PJ, Ju BG, Telese F, Wang X, Glass CK, Rosenfeld MG. Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions. Nature. 2009 Apr 2;458(7238):591-6. doi: 10.1038/nature07849. Epub 2009 Feb 22. PMID:19234442 doi:10.1038/nature07849
- ↑ Kajiwara Y, Akram A, Katsel P, Haroutunian V, Schmeidler J, Beecham G, Haines JL, Pericak-Vance MA, Buxbaum JD. FE65 binds Teashirt, inhibiting expression of the primate-specific caspase-4. PLoS One. 2009;4(4):e5071. doi: 10.1371/journal.pone.0005071. Epub 2009 Apr 3. PMID:19343227 doi:10.1371/journal.pone.0005071
- ↑ Radzimanowski J, Ravaud S, Schlesinger S, Koch J, Beyreuther K, Sinning I, Wild K. Crystal structure of the human Fe65-PTB1 domain. J Biol Chem. 2008 Aug 22;283(34):23113-20. Epub 2008 Jun 11. PMID:18550529 doi:http://dx.doi.org/10.1074/jbc.M800861200
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