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Bioinformatics Forum: Mapping the Interaction Network of the ASPP Family
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Hadar Benyamini and Assaf Friedler (The Institute of Chemistry, The Hebrew University of Jerusalem)
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Monday, 14.9.2009, 13:00
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Biology Auditorium, Technion
The ASPP family proteins have a key role in apoptosis regulation. ASPP1 and ASPP2 promote, while iASPP inhibits p53 mediated apoptosis. ASPP stands for _A_poptosis _S_timulating_P_rotein of _ p_53, as well as representing the domain constitution: _A_nkyrin repeats, _S_H3 and _P_roline rich containing _P_rotein. The ankyrin repeats and SH3 domains (Ank-SH3) mediate the interactions of the ASPP family members with major apoptosis regulators, including p53, Bcl-2 and NFκB. We studied the structure and interactions of ASPP2 using biophysical, biochemical and bioinformatics methods in order to elucidate its interaction network and regulation. We have shown that the proline rich domain of ASPP2 is natively unfolded and revealed an intra molecular interaction between the proline rich and the ANK-SH3 of ASPP2. This interaction has a role in regulating the intermolecular interactions of ASPP2 with other proteins (/1/). We quantitatively characterized the interaction of ASPP2 with Bcl-2, mapped the binding sites and suggested a structural model for the complex that explained the mechanism of action (/2/). Furthermore, we provided a structural model for the interaction of ASPP2 with NFκB based on peptide binding data, protein docking and molecular dynamics (/3/). Competition assays validated the structural models for the interactions of ASPP2 Ank-SH3 with the proine-rich domain, Bcl-2 and NFκB. Finally, we moved from the ASPP2 level to the ASPP family level and compared the sequences of the protein family members at the protein binding site to find the basis for the functional diversity in the family (/4/). We found a subset of residues that differentiate ASPP1/2 from iASPP. These residues are mainly surface exposed and contain mainly electrostatic changes. The most prominent feature is gain of negative charge in ASPP1/2 compared to iASPP, which appears to convey them better binding affinity to p53, Bcl-2 and NFκB. Our studies provide a structural map for the interaction network of ASPP2 and reveal a conserved set of residues that differentiate pro- from anti-apoptotic members of the ASPP family.
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