The ASPP interaction network: Electrostatic differentiation between pro- and anti-apoptotic proteins

Hadar Benyamini, Assaf Friedler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

The ASPP proteins are apoptosis regulators: ASPP1 and ASPP2 promote, while iASPP inhibits, apoptosis. The mechanism by which these different outcomes are achieved is still unknown. The C-terminal ankyrin repeats and SH3 domain (ANK-SH3) mediate the interactions of the ASPP proteins with major apoptosis regulators such as p53, Bcl-2, and NFκB. The structure of the complex between ASPP2ANK-SH3 and the core domain of p53 (p53CD) was previously determined. We have recently characterized the individual interactions of ASPP2ANK-SH3 with Bcl-2 and NFκB, as well as a regulatory intramolecular interaction with the proline rich domain of ASPP2. Here we compared the ASPP interactions at two levels: ASPP2ANK-SH3 with different proteins, and different ASPP family members with each protein partner. We found that the binding sites of ASPP2 to p53CD, Bcl-2, and NFκB are different, yet lie on the same face of ASPP2ANK-SH3. The intramolecular binding site to the proline rich domain overlaps the three intermolecular binding sites. To reveal the basis of functional diversity in the ASPP family, we compared their protein-binding domains. A subset of surface-exposed residues differentiates ASPP1 and ASPP2 from iASPP: ASPP1/2 are more negatively charged in specific residues that contact positively charged residues of p53CD, Bcl-2, and NFκB. We also found a gain of positive charge at the non-protein binding face of ASPP1/2, suggesting a role in electrostatic direction towards the negatively charged protein binding face. The electrostatic differences in binding interfaces between the ASPP proteins may be one of the causes for their different function.

Original languageAmerican English
Pages (from-to)266-274
Number of pages9
JournalJournal of Molecular Recognition
Volume24
Issue number2
DOIs
StatePublished - Mar 2011

Keywords

  • ASPP
  • ASPP2
  • Bcl-2
  • NF-kappa-B
  • computational studies
  • iASPP
  • interaction network
  • p53

Fingerprint

Dive into the research topics of 'The ASPP interaction network: Electrostatic differentiation between pro- and anti-apoptotic proteins'. Together they form a unique fingerprint.

Cite this