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PDBsum entry 2m8s
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Chaperone/membrane protein
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PDB id
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2m8s
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References listed in PDB file
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Key reference
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Title
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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).
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Authors
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K.W.Hung,
H.W.Huang,
C.C.Cho,
S.C.Chang,
C.Yu.
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Ref.
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Biochemistry, 2014,
53,
1935-1946.
[DOI no: ]
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PubMed id
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Abstract
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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.
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