Abstract
We present a possible molecular basis for the opposite activity of two homologues proteins that bind similar ligands and show that this is achieved by fine-tuning of the interaction interface. The highly homologous ASPP proteins have opposite roles in regulating apoptosis: ASPP2 induces apoptosis while iASPP inhibits it. The ASPP proteins are regulated by an autoinhibitory interaction between their Ank-SH3 and Pro domains. We performed a detailed biophysical and molecular study of the Pro-Ank-SH3 interaction in iASPP and compared it to the interaction in ASPP2. We found that iASPP Pro is disordered and that the interaction sites are entirely different: iASPP Ank-SH3 binds iASPP Pro via its fourth Ank repeat and RT loop while ASPP2 Ank-SH3 binds ASPP2 Pro via its first Ank repeat and the n-src loop. It is possible that by using different moieties in the same interface, the proteins can have distinct and specific interactions resulting in differential regulation and ultimately different biological activities.
| Original language | English |
|---|---|
| Article number | 11629 |
| Journal | Scientific Reports |
| Volume | 5 |
| DOIs | |
| State | Published - 1 Jul 2015 |
Bibliographical note
Funding Information:A.F. is supported by grants from the Israel science foundation, the Israel cancer association, Israel cancer research foundation (ICRF) and the Minerva Center for Bio-hybrid complex systems. A.I. is supported by the Dalia and Dan Maydan Fellowship for advanced degree students at the Hebrew University of Jerusalem.