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Nuclear magnetic resonance structure of the cytoplasmic tail of heparin binding EGF-like growth factor (proHB-EGF-CT) complexed with the ubiquitin homology domain of Bcl-2-associated athanogene 1 from Mus musculus (mBAG-1-UBH).
- Source :
-
Biochemistry [Biochemistry] 2014 Apr 01; Vol. 53 (12), pp. 1935-46. Date of Electronic Publication: 2014 Mar 24. - Publication Year :
- 2014
-
Abstract
- The membrane form of heparin binding EGF-like growth factor (proHB-EGF) yields secreted HB-EGF and a membrane-anchored cytoplasmic tail (proHB-EGF-CT), which may be targeted to the nuclear membrane after a shedding stimulus. Bcl-2-associated athanogene 1 (BAG-1) accumulates in the nuclei and inhibits apoptosis in adenoma-derived cell lines. The maintenance of high levels of nuclear BAG-1 enhances cell survival. However, the ubiquitin homology domain of BAG-1 from Mus musculus (mBAG-1-UBH) is proposed to interact with proHB-EGF-CT, and this interaction may enhance the cytoprotection against the apoptosis inducer. The mechanism of the synergistic anti-apoptosis function of proHB-EGF-CT and mBAG-1-UBH is still unknown. We offer a hypothesis that proHB-EGF-CT can maintain high levels of nuclear BAG-1. In this study, we first report the three-dimensional nuclear magnetic resonance structure of proHB-EGF-CT complexed with mBAG-1-UBH. In the structure of the complex, the residues in the C-terminus and one turn between β-strands β1 and β2 of mBAG-1-UBH bind to two terminals of proHB-EGF-CT, which folds into a loop with end-to-end contact. This end-to-end folding of proHB-EGF-CT causes the basic amino acids to colocalize and form a positively charged groove. The dominant forces in the binding interface between proHB-EGF-CT and mBAG-1-UBH are charge-charge interactions. On the basis of our mutagenesis results, the basic amino acid cluster in the N-terminus of proHB-EGF-CT is the crucial binding site for mBAG-1-UBH, whereas another basic amino acid in the C-terminus facilitates this interaction. Interestingly, the mBAG-1-UBH binding region on the proHB-EGF-CT peptide is also involved in the region found to be important for nuclear envelope targeting, supporting the hypothesis that proHB-EGF-CT is most likely able to trigger the nuclear translocation of BAG-1 in keeping its level high.
- Subjects :
- Amino Acid Sequence
Animals
Binding Sites genetics
Cell Survival genetics
Cytoplasm chemistry
Cytoplasm genetics
Cytoplasm metabolism
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
Genes, bcl-2
Heparin-binding EGF-like Growth Factor
Intercellular Signaling Peptides and Proteins genetics
Intercellular Signaling Peptides and Proteins metabolism
Mice
Molecular Sequence Data
Sequence Homology, Amino Acid
Transcription Factors genetics
Transcription Factors metabolism
Ubiquitin genetics
Ubiquitin metabolism
DNA-Binding Proteins chemistry
Intercellular Signaling Peptides and Proteins chemistry
Magnetic Resonance Spectroscopy methods
Transcription Factors chemistry
Ubiquitin chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4995
- Volume :
- 53
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 24628338
- Full Text :
- https://doi.org/10.1021/bi5003019